Salts of 3-azabicyclo[3.3.1]nonanes as antiarrhythmic agents, and precursors thereof

ABSTRACT

Salts of 3-azabicyclo[3.3.1]nonanes are used in controlling antiarrhythmic processes and precursors thereof are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of Ser. No. 07/435,976 filedNov. 13, 1989, now U.S. Pat. No. 5,084,572.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to antiarrhythmic compositions. Specifically,this invention relates to certain derivatives of3-azabicyclo[3.3.1]nonanes.

2. Description of the Prior Art

3-Azabicyclo[3.3.1]nonanes with heteroatoms such as N, S, and O at the7-position are known and documented in the chemical literature. A reviewin Chemical Reviews, Volume 81, No. 2, pages 149-174 (1981), entitled"Chemistry of 3-Azabicyclo[3.3.1]nonanes" by R. Jeyaraman and S. Avila,covers the synthesis, reactions and stereochemistry of the titlecompounds. The review acknowledges the close resemblance of3-azabicyclo[3.3.1]nonanes (3-ABN) to aza- and diazaadamantanes inconformation and stereochemistry, and this has caused progress in thechemistry of the title compounds. The review further acknowledges that3-ABN systems can be obtained by a Mannich, or modified Mannich,reaction involving a condensation of ketones or aldehydes with a primaryamine under relatively mild conditions. Thus, the availability of avariety of ketones or aldehydes has prompted studies on 3-ABNs.

According to the chemical literature, a few derivatives of 3-ABN haveexhibited useful biological properties. Potent analgesic and antitusivecharacteristics as well as antagonism to analgesic effects and tonarcotic action have been observed, depending upon the groups attachedto the basic structure. In addition, some examples have displayedsedative action as well as antipyretic and hypoglycemic activity. Simple3-ABN has been reported to be effective against influenza infection.Some derivatives have recorded antiarrhythmic properties. Certainsulfur-substituted, as well as selenium-substituted examples, have beenreported as accessible via a Mannich reaction or a modified Mannichreaction. In U.S. Pat. No. 4,581,361 and U.S. Pat. No. 4,778,892, forexample, such materials are disclosed and claimed as antiarrhythmicagents.

SUMMARY OF THE INVENTION

The present invention involves novel derivatives of3-azabicyclo[3.3.1]nonanes having the basic formula:

    __________________________________________________________________________     ##STR1##                                                                     Y            Z     R      Q    Number                                         __________________________________________________________________________    PhC(O)N      CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (1)                                            4-ClC.sub.6 H.sub.4 C(O)N                                                                  CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (2)                                            3,4-(H.sub.3 CO).sub.2 C.sub.6 H.sub.3 C(O)N                                               CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (3)                                            3,4,5-(H.sub.3 CO).sub.3 C.sub.6 H.sub.2 C(O)N                                             CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (4)                                            PhCH.sub.2 N CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (5)                                            4-ClC.sub.6 H.sub.4 CH.sub.2 N                                                             CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (6)                                            3,4-(H.sub.3 CO).sub.2 C.sub.6 H.sub.3 CH.sub.2 N                                          CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (7)                                            S            CH.sub.2                                                                            (H.sub.3 C).sub.2 CH                                                                 CH.sub.2                                                                           (8)                                            S            CH.sub. 2                                                                           3-I-C.sub.6 H.sub.4 CH.sub.2                                                         CH.sub.2                                                                           (9)                                             ##STR2##    CH.sub.2                                                                            PhCH.sub.2                                                                           CH.sub.2                                                                           (10)                                           S            C(OCH.sub.3).sub.2                                                                  PhCH.sub.2                                                                           CH.sub.2                                                                           (11)                                           PhCH.sub.2 N C(OCH.sub.3).sub.2                                                                  PhCH.sub.2                                                                           CH.sub.2                                                                           (12)                                           C.sub.2 H.sub.5 O(O)C                                                                      CH.sub.2                                                                            PhCH.sub.2                                                                           CH.sub.2                                                                           (13)                                           C.sub.2 H.sub.5 O(O)C                                                                       ##STR3##                                                                           PhCH.sub.2                                                                           CH.sub.2                                                                           (14)                                           S            CH.sub.2                                                                            PhC(O) CH.sub.2                                                                           (15)                                            ##STR4##    C(OCH.sub.3).sub.2                                                                  PhCH.sub.2                                                                           CH.sub.2                                                                           (16)                                           PhCH.sub.2 N CH.sub.2                                                                            PhCH.sub.2                                                                           CO   (17)                                           __________________________________________________________________________

The present invention also provides for novel intermediates of the classof 3-azabicyclo[3.3.1]nonan-9-ones having the formula:

    ______________________________________                                         ##STR5##                                                                     Y           R               Number                                            ______________________________________                                        S           CH.sub.2 Ph     (18)                                              NCH.sub.2 Ph                                                                              CH.sub.2 Ph     (19)                                              CHCO.sub.2 Et                                                                             CH.sub.2 Ph     (20)                                              NCH(CH.sub.3).sub.2                                                                       CH.sub.2 Ph     (21)                                              NCH(CH.sub.3).sub.2                                                                       CH.sub.2 C.sub.6 H.sub.4 -4-Cl                                                                (22)                                              NCH(CH.sub.3).sub.2                                                                       CH.sub.2 C.sub.6 H.sub.3 -3,4-(OCH.sub.3).sub.2                                               (23)                                              NCH(CH.sub.3).sub.2                                                                       CH.sub.2 C.sub.6 H.sub.2 -3,4,5-(OCH.sub.3).sub.3                                             (24)                                              S           CH.sub.2 C.sub.6 H.sub.4 -3-I                                                                 (25)                                              S           CH(CH.sub.3).sub.2                                                                            (26)                                              ______________________________________                                    

The invention further provides additional 3-azabicyclo[3.3.1]nonanes ofthe formula:

    ______________________________________                                         ##STR6##                                                                     Y         Z      R                 Number                                     ______________________________________                                        S         CH.sub.2                                                                             CH.sub.2 Ph       (27)                                       S         CH.sub.2                                                                             H                 (28)                                       S         CH.sub.2                                                                             C(O)Ph            (29)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             CH.sub.2 Ph       (30)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             H                 (31)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             C(O)Ph            (32)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             C(O)C.sub.6 H.sub.4 -4-Cl                                                                       (33)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             C(O)C.sub.6 H.sub.3 -3,4-(OCH.sub.3).sub.2                                                      (34)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             C(O)C.sub.6 H.sub.2 -3,4,5-(OCH.sub.3).sub.2                                                    (35)                                       NCH(CH.sub.3).sub.2                                                                     CH.sub.2                                                                             S(O).sub.2 Ph     (36)                                       NCH.sub.2 Ph                                                                            CH.sub.2                                                                             CH.sub.2 Ph       (37)                                       CHCO.sub.2 Et                                                                           CH.sub.2                                                                              ##STR7##         (38)                                       ______________________________________                                    

Specifically, the invention relates to the above salts (1)-(17) ofcertain 3-azabicyclo[3.3.1]nonanes and precursors (18)-(38) as used incontrolling antiarrhythmic processes. Thus, it is the object of thepresent invention to provide novel compositions that display biologicalactivity. Fulfillment of this object and the presence and fulfillment ofother objects will be apparent upon complete reading of thespecifications and claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The chemical compositions according to the preferred embodiments of thisinvention are heteronuclear ring organic compounds based on the3-azabicyclo[3.3.1]nonane structures as follows: ##STR8##

Wherein the 3-position in general structures (39-41) is nitrogen [asspecifically in (1-38)], the 7-position includes nitrogen [asspecifically in (1-7), (12), (17), (19), (21-24), and (30-37)], sulfur[as specifically in (8-11), (15), (16), (18), and (25-29)], and carbon[as specifically in (13), (14), (20), and (38)]. With nitrogen in the 3-or 7-position, a N--C bond is always present except for (28) and (31)which have N--H bonds and (36) which has an N--S bond. The 9-positioncan be preferably unsubstituted [as specifically in (1)-(10), (13),(15), (17), and (27)-(38)], 9-one [as specifically in (18)-(26)],9,9-dimethoxy [as specifically in (11), (12), and (16)], or a1,3-dithiolane [as specifically in (14) and (38)]. The alkylatednitrogen atom at the 3-position [as specifically in (1)-(16)] and theircorresponding tertiary amine acid salts [hydroperchlorate, HCl, HBr, H₂SO₄, citrate, and fumarate] are included along with a system containingan alkylated nitrogen at the 7-position as in (17) and the correspondingsalts.

These compounds are the active ingredients for potential drugs and/orintermediates for the active ingredients of potential drugs to use inthe treatment of disorders of the heart. They exhibit good activity inanimal models and as such are viable candidates to controllife-threatening arrhythmias found in humans who experience heartattacks or major infarctions of the heart.

Typically, the 9-one systems shown by the general formula (39) [asspecifically in (18)-(26)] are synthesized by the reaction of atetrahydro-4-heteracyclohexanone in the presence of an aldehyde andamine or ammonium salt in accordance with a Mannich or Mannich typereaction. For example, and as illustrated in the following reactionscheme A, 1-isopropyl-4-piperidinone (42) [or 1-benzyl-4-piperidinone(43) or 4-thianone (44)] was allowed to react with benzylamine,4-chlorobenzylamine, 3,4-dimethoxybenzylamine,3,4,5-trimethoxybenzylamine, and the like with paraformaldehyde in thepresence of acetic acid/methanol to produce the3-azabicyclo[3.3.1]nonan-9-ones (39) [representative examples are (18),(19), and (21)-(24)]. The ketone (39) is then reduced with hydrazinehydrate in triethylene glycol/potassium hydroxide media to give membersof (40) which could be reacted with perchloric acid, hydrochloric acid,hydrobromic acid, sulfuric acid, citric acid, or fumaric acid inbenzene, ether, and/or isopropyl alcohol to yield the correspondinghydroperchlorate, hydrochloride, hydrosulfate, citrate, or fumaratederivative (41). Related examples where Y is benzyl or sulfur followsimilarly. Thus the method is applicable to obtain members of (18)-(26),with the exception of (20) which was prepared from ##STR9## the enaminein scheme B starting from (43). The co-reactant with (43) to give (20)is made by ##STR10## treatment of ester (45) with hydrobromic acid togive acid (46) under standard conditions. Esterification of (46) underthe usual conditions produced dibromide (47) which was condensed withthe enamine in the presence of triethylamine in acetonitrile to yieldketone (20) under the usual conditions.

Reduction of the ketones in scheme A, including ketone (20), viaWolff-Kishner conditions, as illustrated with hydrazine/KOH intriethylene glycol, leads to amines of general formula (40)[specifically (27), (30), and (37) are representative examples].Addition of perchloric acid [or HCl, HBr, H₂ SO₄, citric acid, orfumaric acid] in benzene or isopropyl alcohol gives members of generalformula (41) [(5)-(9), and (13) are representative examples].

In reaction scheme C, members of (40) [representative examples are (28),(29), (31), and (32)-(36)] were obtained as outlined. Specific membersof the family of (40) with an N--H bond [note these examples arerepresentative starting materials for the amide systems], namely (28)and ##STR11## (31) as representative examples, are isolable directlyfrom the reaction mixture after workup. Direct aroylation or sulfonationof these types of intermediates (40) in a two-phase system undermodified Schotten-Baumann conditions, or phase transfer conditions,leads to amide members of (39) [(29), (32)-(35), and (36) arerepresentative examples]. Treatment of these latter amide members of(40), such as (32)-(35) and related systems, with perchloric acid, HCl,HBr, H₂ SO₄, citric acid, or fumaric acid in benzene, ether, and/orisopropyl alcohol produces salts (41) illustrated by (1)-(4) asrepresentative examples.

Ketal formation from members of (39), using methanol or1,2-ethanedithiol, under standard conditions, produced members of (40),such as illustrated with (38) as a representative example, or, aftertreatment with perchloric acid, HCl, HBr, H₂ SO₄, citric or fumaricacid, produced members of (41) such as illustrated with (11), (12),(14), and (16) as representative examples.

Since oxidation products are viable candidates as potential metabolitesfrom use of these compounds in animals, including humans, oxidation ofspecific sites was performed. As an example, oxidation of (37)illustrates the introduction of an oxygen atom alpha to the nitrogenwhen treated with RuO₂ xH₂ O/NaIO₄ in a water/carbon tetrachloridemixture to produce lactam (17). Moreover, oxidation of sulfur to givemembers of (41), with sulfoxides (10) and (16) as representativeexamples, can lead to potential metabolites. Salt formation is againeffected by the method outlined previously for members of (41).

EXAMPLE I 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (18)

Ketone (18) was prepared by the method in U.S. Pat. No. 4,581,361.

EXAMPLE II 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane (27)

This amine (27) was prepared from ketone (18) by the method of Bailey,III, et. al. J. Med. Chem., vol. 27(6) pp. 758-767 (1984).

EXAMPLE III 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane Hydroperchlorate(48)

This amine salt was prepared from amine (27) by the method of Bailey,III, et. al. J. Med. Chem., vol. 27(6) pp. 758-767 (1984).

EXAMPLE IV 3-Thia-7-azabicyclo[3.3.1]nonane (28)

A 50-mL, three-necked, round-bottomed flask was equipped with a magneticstirrer, a heating mantle, a standard condenser with a N₂ inlet and twoglass stoppers. In one portion, anhydrous HCO₂ NH₄ (1.11 g, 17.1 mmol)was added under N₂ to a mixture of the amine (27, 0.90 g, 3.86 mmol) and10% Pd/C (0.90 g) in anhydrous CH₃ OH (25 mL). With stirring, themixture was brought to reflux for 30 min, filtered through a Celite padon a fritted funnel (which was washed thoroughly with CH₂ Cl₂), and thenconcentrated to give a gummy oil with suspended solid. This material wasagain dissolved in CH₂ Cl₂ (˜15 mL), and the suspension was filtered toremove any unreacted ammonium formate. The filtrate was thenconcentrated to near saturation and placed in a diffusion chamber ofether overnight. Crude amine (28) became an oil; however, the motherliquor, containing predominantly starting material, could be decanted.Chromatography of the oil employed a gradient elution of CH₃ OH/CH₂ Cl₂(300 mL of 10% CH₃ OH/CH₂ Cl₂, 50 mL of 20% CH₃ OH/CH₂ Cl₂, 100 mL of50% CH₃ OH/CH₂ Cl₂, and 100 mL of CH₃ OH) on silica gel (35 g, 1.5 cm×62cm) and afforded 0.32 g (56.9%) of amine (28) (R_(f) =0.11, 10% CH₃OH/CH₂ Cl₂) as a light, gummy solid which was used without furtherpurification. ¹ H NMR (DCCl₃) δ1.84, 2.04 [two bd, 2H, H(9)], 2.31 [bs,2H, H(1,5)], 2.80 [bd, 2H, H(2,4)_(ax), J=12.3 Hz], 3.20 [bd, 2H,H(2,4)_(eq), J=13.7 Hz], 3.45 [m, 2H, H(6,8)_(ax) ], 3.73 [bd, 2H,H(6,8)_(eq), J=13.2 Hz], 7.59 (bs, 1H, N-H); ¹³ C NMR (DCCl₃) ppm 24.88[d, C(1,5)], 29.79 [t, C(9)], 32.17 [t, C(2,4)], 47.8 [t, C(6,8)].

EXAMPLE V 7-Benzoyl-3-thia-7-azabicyclo[3.3.1]nonane (29)

A 10-mL, two-necked, round-bottomed flask was equipped with a magneticstirrer, an ice bath, a standard condenser with a N₂ inlet, and a glassstopper. To a chilled (5° C.) solution of NaOH pellets (0.1 g, 2.38mmol) in H₂ O (1.7 mL) was added a solution of the amine (28, 0.17 g,1.19 mmol) in CH₂ Cl₂ (1 mL). This was followed by the dropwise additionof a solution of benzoyl chloride (0.2 g, 1.43 mmol) over ˜5 min. Afterstirring for 30 min at 0°-5° C., 30 min at RT, and then 15 min over asteam bath, the mixture was diluted with H₂ O (15 mL), and the mixturewas extracted (CH₂ Cl₂, 3×15 mL). Combining the extracts, drying (Na₂SO₄, overnight), filtering, and concentrating the solution gave aviscous yellow oil. Chromatography of the oil on alumina (38 g, 2.4cm×17 cm) employed ethyl acetate as eluant and afforded amide (29)(R_(f) =0.47) as white crystals (157 mg, 53.3%); mp 95°-96° C. IR (KBr)cm⁻¹ 3065, 3045 (Ar C--H), 3000, 2985, 2940, 2910, 2855, 2835 (C--H),1635 (C═O), 745, 720 (C--H out of plane, mono); ¹ H NMR (DCCl₃)δ1.78-1.93 [m, 3H, H(9) and H(1)], 2.15 [bs, 1H, H(5)], 2.39 [d, 1H,H(4)_(ax), J=13.9 Hz], 2.77 [d, 1H, H(6)_(ax), J=12.3 Hz], 3.12-3.21 [m,3H, H(4)_(eq) and H(6)_(eq) ], 3.41 [d, 1H, H(2)_(ax), J=12.8 Hz], 3.89[d, 1H, H(2)_(eq), J=13.4 Hz), 4.98 [d, 1H, H(8)_(eq), J=13.1 Hz],7.38-7.44 [m, 5H, Ar--H]; ¹³ C NMR (DCCl₃) ppm 26.53 [C(1)], 26.87[C(5)], 31.73 [C(2)], 31.78 [C(9)], 32.34 [C(4)], 46.07 [C(8)], 52.12[C(6)], 126.46, 128.41, 128.83, 137.35 (Ar--C), 170.38 [C═O]. Anal.Calcd. for C₁₄ H₁₇ NOS: C, 67.98; H, 6.93. Found: C, 68.01; H, 7.07.

EXAMPLE VI 7-Benzyl-3-isopropyl-3,7-diazabicyclo[3.3.1]nonan-9-one (21)

A 500-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a 250-mL addition funnel, a standardcondenser with a N₂ inlet and a glass stopper. A mixture of benzylamine(10.71 g, 100 mmol), HCl (37%, 9.86 g, 100 mmol), glacial acetic acid(3.0 g, 50 mmol) and paraformaldehyde (6.31 g, 210 mmol) in deoxygenated(N₂ bubbled in for 1 h) CH₃ OH (100 mL) was stirred at reflux for 15 minunder N₂. A solution of 1-isopropyl-4-piperidinone (42, 14.12 g, 100mmol) and glacial acetic acid (6.0 g, 100 mmol) in CH₃ OH (100 mL) wasthen added dropwise to the mixture over 30 min, followed by stirring atreflux for an additional 18.5 h. Concentration of the solution gave anoil which was redissolved in H₂ O (100 mL). An ether extract (100 mL) ofthis acidic solution was discarded. Basicification (pH˜13) of the waterlayer was achieved by the addition of 10% NaOH, resulting in theformation of a milky suspension which was extracted (ether, 4×60 mL).Combined extracts were dried (Na₂ SO₄, 1 h), filtered, and concentratedto a viscous red oil, which, when distilled (175°-185° C./10⁻⁵ mm Hg),afforded a light yellow oil (15.6 g, 57.2%) that solidified whenrefrigerated at -10° C.; mp 46°-47.5° C. This solid could berecrystallized (pentane) to give an analytical sample of ketone (21); mp49°-50° C. IR (KBr) cm⁻¹ 3095, 3070, 3035 (Ar--H), 2975, 2900, 2820(C--H), 1745 (C═O), 1605, 1495 (C═C), 740, 700 (C--H out of plane,mono); ¹ H NMR (DCCl₃) δ1.02 (d, 6H, CH₃), 2.58 [bs, 2H, H(1,5 )], 2.87[m, 5H, ring protons and CH(CH₃)₂ ], 3.03 (dd, 4H, ring protons), 3.53(s, 2H, ArCH₂), 7.30 (m, 5H, Ar--H); ¹³ C NMR (DCCl₃) ppm 18.25 (CH₃),46.93 [C(1,5)], 53.41 [CH(CH₃)₂ ], 53.71 [C(2,4)], 58.07 [C(6,8)], 61.25(ArCH₂), 127.09, 128.25, 128.69, 138.67 (Ar--C), 215.20 (C═O); ¹⁵ N NMR(DCCl₃) ppm 39.25 [N(7)], 40.80 [N(3)]. Anal. Calcd. for C₁₇ H₂₄ N₂ O:C, 74.96; H, 8.88; N, 10.28. Found: C, 75.18; H, 8.61; N, 10.24.

EXAMPLE VII 7-Benzyl-3-isopropyl-3,7-diazabicyclo[3.3.1]nonane (30)

To a mixture of KOH pellets (85%, 11.62 g, 176 mmol) and the ketone (21)(6.0 g, 22 mmol) in triethylene glycol (100 mL) was added hydrazine(95%, 2.97 g, 88 mmol) in one portion in a 200-mL, jacketed flaskequipped with a magnetic stirrer, a heating mantle, a standardcondenser, a lower take-off condenser with a N₂ inlet, and two glassstoppers. A heating temperature of 200°-210° C. for 4 h under N₂ wasproduced by boiling tetralin (bp 207° C.) in the jacket. Cooling of thesolution to RT was followed by the addition of chilled water (125 mL).Combined extracts (ether, 4×50 mL) of the suspension were washed with10% NaOH (50 mL) and saturated NaCl (50 mL), dried (Na₂ SO₄, 1 h),filtered, and concentrated (rotary evaporator then vacuum pump,overnight, RT/0.2 mm Hg) to a yellow oil (5.53 g, 97.3%). Analysis ofthe very slight crude amine (30) showed no carbonyl stretch in the IRspectrum, and thus it was used without further purification.

EXAMPLE VIII 7-Benzyl-3-isopropyl-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (5)

A 125-mL Erlenmeyer flask was equipped with a magnetic stirrer and anice bath. To a stirred, chilled (5° C.) solution of the amine (30, 0.84g, 3.25 mmol) in dry ether (50 mL) was added dropwise a solution ofHClO₄ (60%, 1.08 g, 6.50 mmol) in isopropyl alcohol (3 mL) over 20 min.After the mixture was stirred an additional hour, a white powderymaterial was filtered, and then dissolved in CH₃ OH. Decolorizing withNorit, filtering, and concentrating the solution gave a solid that wasrecrystallized (CH₃ OH) to give 0.65 g (49.4%) of salt (5); mp152.0°-152.5° C. IR (KBr) cm⁻¹ 3050, 3030 (Ar C--H), 2970, 2940, 2910,2810 (C--H), 1090 (Cl--O); ¹ H NMR (DMSO-d₆) δ1.18 (d, 6H, CH₃), 1.62[d, 1H, H(9), J=12.4 Hz], 1.82 [d, 1H, H(9), J=12.7 Hz], 2.14 [bs, 2H,H(1,5)], 2.47 [d, 2H, H(6,8)_(ax), J=11.4 Hz], 3.11 [m, 4H, H(2,4)_(ax)and H(6,8)_(eq) ], 3.32 [d, 2H, H(2,4)_(eq), J=11.8 Hz], 3.47 [h, 1H,CH(CH₃)₂ ], 3.52 (s, 2H, ArCH₂), 7.30-7.46 (m, 5H, Ar--H); ¹³ C NMR(DMSO-d₆) ppm 16.11 (q, CH₃), 27.24 [d, C(1,5)], 29.67 [t, C(9)], 52.85[t, C(2,4[, 56.00 [d, CH(CH₃)₂ ], 56.85 [t, C(6,8)], 61.15 (t, ArCH₂),127.65, 128.35, 129.38, 136.35 (Ar--C); ¹⁵ N NMR (DMSO-d₆) ppm 50.90[N(7)], 60.47 [N(3)]. Anal. Calcd. for C₁₇ H₂₇ ClN₂ O₄ : C, 56.90; H,7.58; N, 7.81. Found: C, 56.70; H, 7.45; N, 7.84.

EXAMPLE IX 3-Isopropyl-3,7-diazabicyclo[3.3.1]nonane (31)

A 200-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a condenser with a N₂ inlet, and twoglass stoppers. To a stirred mixture of amine (30) (5.53 g, 21.4 mmol)and 10% Pd/C (0.64 g, 30 mg/mmol of amine) in CH₃ OH (80 mL) was addedanhydrous HCO₂ NH₄ (3.37 g, 53.5 mmol) in one portion. Stirring themixture at reflux under N₂ for 30 min, cooling the new mixture to RT,and filtering through a celite pad was followed by concentration of theresulting solution to give a viscous oil. The oil was then dissolved inH₂ O (80 mL) and the pH was adjusted to ˜12 by the addition of 10% NaOH.Combined extracts (CH₂ Cl₂, 4×40 mL) of the aqueous solution were dried,filtered, and concentrated (rotary evaporator then vacuum pump, 10 min,RT/0.2 mm Hg) to give amine (31) as a light oil (3.35 g, 93.0%) whichwas used without further purification. IR (film) cm⁻¹ 3315 (N--H), 2965,2900, 2850, 2790, 2760, 2725 (C--H); ¹ H NMR (DCCl₃) δ1.01 (d, 6H, CH₃,J=6.7 Hz), 1.60-1.67 [m, 3H, H(1,5) and H(9)], 2.53-2.59 [m, 3H, ringprotons and CH(CH₃)₂ ], 2.90-3.06 [m, 6H, ring protons], 3.56 (bs, 1H,N--H); ¹³ C NMR (DCCl₃) ppm 18.12 (CH₃), 30.04 [C(1,5)], 33.62 [C(9)],52.86 [C(6,8)], 54.59 [CH(CH₃)₂ ], 54.65 [C(2,4)].

EXAMPLE X 3-Benzoyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane (32)

A three-necked, 50-mL, round-bottomed flask was equipped with a magneticstirrer, an ice bath, a standard condenser with a N₂ inlet, and twoglass stoppers. To a solution of 10% NaOH (8.94 g, 22.3 mmol) was addedthe amine (31, 1.14 g, 6.77 mmol) in CH₂ Cl₂ (15 mL) in one portion.Dropwise addition of a solution of benzoyl chloride (1.05 g, 7.45 mmol)in CH₂ Cl₂ (5 mL) to the mixture over 15 min under N₂ was followed bystirring an additional 2.75 h at RT. After the addition of H₂ O (30 mL),the organic layer was separated. Additional extracts (CH₂ Cl₂, 3×25 mL)were combined with the initial organic layer, dried (Na₂ SO₄, 1 h),filtered, and concentrated (aspirator followed by vacuum pump, 1 h,RT/0.2 mm Hg) to give an orange oil. Chromatography of the oil wasperformed over neutral alumina (200 g, 2.1 cm×33 cm) with ethyl acetateas eluant. Fractions (R_(f) =0.70) were combined and concentrated(rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to yield1.52 g (82.4%) of the amide (32) as an oil which was used withoutfurther purification. IR (film) cm⁻¹ 3085, 3065, 3035 (Ar C--H), 2970,2925, 2865, 2805, 2780, 2750 (C--H), 1635 (C═O), 730, 710 (C--H out ofplane, mono); ¹ H NMR (DCCl₃) δ0.96 (d, 3H, CH₃, J=6.4 Hz), 1.07 (d, 3H,CH₃, J=6.6 Hz), 1.65-1.78, [m, 3H, H(5) and H(9)], 1.97 [bs, 1H, H(1)],2.41 [d, 1H, H(4)_(ax), J=10.3 Hz], 2.50 [d, 1H, H(6)_(ax), J=11.0 Hz] ,2.62 [m, 1H, CH(CH₃)₂, J=6.5 Hz], 2.72 [d, 1H, H(6)_(eq), J=10.6 Hz],3.04-3.07 [m, 2H, H(2)_(ax) and H(4)_(eq) ], 3.30 [d, 1H, H(8)_(ax),J=13.2 Hz], 3.74 [d, 1H, H(8)_(eq), J=12.8 Hz], 4.77 [d, 1H, H(2)_(eq),J=13.9 Hz], 7.28-7.41 (m, 5H, Ar--H); ¹³ C NMR (DCCl₃) ppm 16.30 (CH₃),19.33 (CH₃), 29.06 [C(1)], 29.76 [C(5)], 32.29 [C(9)], 46.55 [C(2)],52.19 [C(4)], 52.62 [C(8)], 54.34 [CH(CH₃ )₂ ], 54.75 [C(6)], 126.75,128.24, 128.67, 137.75 (Ar--C), 170.09 (C═O).

EXAMPLE XI 3-Benzoyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (1)

A 250-mL Erlenmeyer flask was equipped with a magnetic stirrer and anice bath. To a chilled (5° C.), stirred solution of the amide (32, 1.52g, 5.58 mmol) in ether (60 mL) was added dropwise HClO₄ (60%, 1.17 g,6.98 mmol) over 10 min. Filtration gave salt (1) as a white solid whichwas washed with dry ether (50 mL), stirred in hot CH₃ OH (30 mL), cooledto -10° C. overnight, filtered, and dried (vacuum pump, 61° C./0.2 mmHg, overnight) to afford 1.90 g (91.3%) of pure salt (1); mp 226°-227°C. (dec): IR (KBr) cm⁻¹ 3150 (N--H), 2990, 2960, 2935, 2920, 2885(C--H), 1635 (C═O), 1100 (Cl--O), 740, 710 (C--H out of plane, mono); ¹H NMR [(D₃ C)₂ C═O] δ1.55 (d, 6H, CH₃, J=6.6 Hz), 1.97 [bd, 1H, H(9),J=13.0 Hz], 2.18 [bd, 1H, H(9), J=13.2 Hz], 2.51 [bs, 2H, H(1,5)], 3.30[bd, 2H, H(2,4)_(ax), J=13.2 Hz], 3.65 [m, 2H, H(6,8)_(ax) ], 3.83 [h,1H, --CH(CH₃)₂, J=6.8 Hz], 3.94 [bd, 2H, H(2,4)_(eq), J=12.3 Hz], 4.23[bd, 2H, H(6,8)_(eq), J=13.2 Hz], 7.45-7.50 (m, 5H, Ar--H), 7.85 (bs,1H, N--H); ¹³ C NMR (DMSO-d₆, 80° C.) ppm 16.34 (CH₃), 26.69 [C(1,5)],27.62 [C(9)] , 48.80 [C(2,4)], 52.31 [C(6,8)], 59.91 [CH(CH₃)₂ ],127.05, 128.30, 129.40, 136.40 (Ar--C), 172.86 (C═O). Anal. Calcd. forC₁₇ H₂₅ ClN₂ O₅ : C, 54.76; H, 6.76. Found: C, 54.43; H, 6.78.

EXAMPLE XII3-(3',4'-Dimethoxybenzyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonan-9-one(23)

A 200-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a standard condenser with a N₂inlet, a 50-mL addition funnel, and a glass stopper. A mixturecontaining 3,4-dimethoxybenzylamine (8.36 g, 50 mmol), paraformaldehyde(3.15 g, 105 mmol) and CH₃ OH (35 mL) was made acidic with the additionof glacial acetic acid (3.0 g, 50 mmol). Stirring the mixture under N₂for 20 min was followed by the dropwise addition of1-isopropyl-4-piperidinone (42, 7.06 g, 50 mmol) and glacial acetic acid(3.0 g, 50 mmol) in CH₃ OH (25 mL) over 1.25 h. Boiling of the mixturewas continuous for an additional 23 h. This new mixture was evaporatedto give a red viscous oil. After dissolving the oil in H₂ O (100 mL),the solution was extracted (ether, 2×100 mL), the latter beingdiscarded. Chilling (ice water bath) of the water layer below 10° C.,followed by basification (pH˜12) with KOH pellets (6.6 g, 100 mmol),produced an orange suspension which was extracted (CH₂ Cl₂, 4×80 mL).Combined extracts were dried (Na₂ SO₄, overnight), filtered, andconcentrated to give a crude oil. This oil was digested in 250 mL ofSkelly B (bp 60°-68° C.) for 0.5 h and the supernatant was decanted.Evaporation of the solvent gave an oil which, when distilled (175°-205°C./10⁻⁴ mm Hg), afforded a yellow oil. Adding Skelly B inducedcrystallization to give 4.32 g (26%) of off white ketone (23); mp79.5°-80.5° C. IR (KBr) cm⁻¹ 3095, 3015 (Ar--H), 2980, 2955, 2920, 2855,2810 (C--H), 1745 (C═O), 1620, 1605 (C═C); ¹ H NMR (DCCl₃) δ1.03 (d, 6H,CH₃, J=6.6 Hz), 2.59 [bs, 2H, H(1,5)], 2.81-2.90 [m, 5H, ring protonsand CH(CH₃)₂ ], 2.98 (dd, 2H, ring protons, J=10.7 Hz, J'=3.2 Hz), 3.08(dd, 2H, ring protons, J=10.7 Hz, J'=2.99 Hz), 3.47 (s, 2H, ArCH₂), 3.87(s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.80-6.92 (m, 3H, Ar--H); ¹³ C NMR(DCCl₃) ppm 18.17 (CH₃), 46.85 [C(1,5)], 53.40 [CH(CH₃)₂ ], 53.86[C(2,4)], 55.76, 55.86 (OCH₃), 58.01 [C(6,8)], 60.93 (ArCH₂), 110.60,111.46, 120.68, 131.30, 148.04, 148.90 (Ar--C), 215.27 (C═O); ¹⁵ N NMR(DCCl₃) ppm 39.66 [N(7)], 40.93 [N(3)]. Anal. Calcd. for C₁₉ H₂₈ N₂ O₃ :C, 68.65; H, 8.49. Found: C, 68.70; H, 8.53.

EXAMPLE XIII7-(3',4'-Dimethoxybenzyl)-3-isopropyl-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (7)

To a mixture of KOH pellets (85%, 2.38 g, 36 mmol) and the ketone (23,1.0 g, 3 mmol) in triethylene glycol (25 mL) was added hydrazine (95%,1.01 g, 30 mmol) in one portion in a 70-mL, jacketed flask equipped witha magnetic stirrer, a heating mantle, a standard condenser, a lowertake-off condenser and two glass stoppers. A heating temperature of150°-160° C. for 3.5 h was achieved by using tetralin (bp 207° C.) inthe jacket. After cooling to RT, the solution was diluted with cold H₂ O(50 mL) and extracted with ether (3×40 mL). Combined extracts werewashed with 10% NaOH (50 mL) and saturated NaCl (50 mL), dried (Na₂ SO₄,overnight), filtered, and concentrated to afford a yellow oil (0.78 g).Dissolution of the oil in ether (50 mL) with magnetic stirring andcooling (5° C., via ice water bath) in a 125-mL Erlenmeyer flask(equipped with an external ice bath) was followed by the dropwiseaddition of a solution of HClO₄ (60%, 0.51 g, 3.06 mmol) over 10 min.Filtering the precipitate, washing the latter with ether (˜50 mL), andthen recrystallizing (95% EtOH) gave 0.79 g (62.9%) of white salt (3);mp 127.5°-128.0° C. (dec). IR (KBr) cm⁻¹ 3020 (Ar C--H), 2955, 2930,2840, 2815, 2790 (C--H), 1610 (C═C), 1090 (Cl--O); ¹ H NMR (DMSO-d₆)δ1.15 (d, 6H, CH₃, J=6.7 Hz), 1.64 [d, 1H, H(9), J=12.1 Hz], 1.80 [d,1H, H(9), J=13.0 Hz], 2.14 [bs, 2H, H(1,5)], 2.50 [d, 2H, H(6,8)_(ax),J=10.4 Hz], 3.05-3.14 [m, 4H, H(6,8)_(eq) and H(2,4)_(ax) ], 3.28 [d,2H, H(2,4)_(eq), J=11.6 Hz], 3.39 [m, 1H, CH(CH₃), J=6.7 Hz], 3.49 (s,2H, ArCH₂), 3.75, 3.76 (two s, 6H, OCH₃), 6.86-7.08 (m, 3H, Ar--H); ¹³ CNMR (DMSO-d₆) ppm 16.25 (CH₃), 27.23 [C(1,5)], 29.79 [C(9)], 52.74[C(2,4)], 55.31, 55.36 (OCH₃), 55.78 [CH(CH₃)₂ ], 56.85 [C(6,8)], 60.89(ArCH₂), 111.23, 113.01, 122.02, 128.00, 148.38, 148.66 (Ar--C); ¹⁵ NNMR (DMSO-d₆) ppm 52.22 [N(7)], 59.43 [N(3)]. Anal. Calcd. for C₁₉ H₃₁ClN.sub. 2 O₆ : C, 54.48; H, 7.46. Found: C, 54.76; H, 7.61.

EXAMPLE XIV7-(4'-Chlorobenzyl)-3-isopropyl-3,7-diazabicyclo[3.3.1]nonan-9-one (22)

A 200-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a standard condenser with a N₂inlet, a 50-mL, an addition funnel and a glass stopper. A mixture of4-chlorobenzylamine (7.08 g, 50 mmol), paraformaldehyde (3.15 g, 105mmol), glacial acetic acid (3.0 g, 50 mmol), and CH₃ OH (35 mL) wasbrought to gentle reflux with stirring under N₂ for 15 min. To themixture was added dropwise a solution of 1-isopropyl-4-piperidinone (42,7.06 g, 50 mmol) and glacial acetic acid (3.0 g, 50 mmol) in CH₃ OH (25mL) over 1 h. Boiling of the mixture was continued for an additional 24h. After concentrating to a viscous red oil, the reaction mixture wasthen diluted with H₂ O (100 mL) and extracted (ether, 3×100 mL), thelatter being discarded. Chilling (via ice water bath) of the aqueouslayer to below 10° C. was followed by basification (pH˜13) with KOHpellets (85%, 6.6 g, 100 mmol). Combined extracts (ether, 3×60 mL) weredried (Na₂ SO₄, 4 h), filtered, and concentrated to give a viscous redoil. This oil was digested in pentane (100 mL) for 20 min and thesupernatant was decanted and concentrated Distillation of the resultingoil (195°-205° C./10⁻⁵ mm Hg) gave 5.25 g of a yellow oil whichsolidified upon standing. Recrystallization (pentane) of the solid gave3.46 g (22.6%) of white crystalline (22); mp 68°-69° C. IR (KBr) cm⁻¹3030 (Ar C--H), 2955, 2880, 2800 (C--H), 1730 (C═O), 800 (C--H out ofplane, para); ¹ H NMR (DCCl₃) δ1.03 (d, 6H, CH₃, J=6.3 Hz), 2.58 [bs,2H, H(1,5)] , 2.80-3.05 [m, 9H, ring protons and CH(CH₃)₂ ], 7.27 (s,4H, Ar--H); ¹³ C NMR (DCCl₃) ppm 18.25 (CH₃), 46.85 [C(1,5)], 53.40[CH(CH₃)₂ ], 53.76 [C(2,4)], 57.92 [C(6,8)], 60.48 (ArCH₂), 128.40,129.95, 132.74, 137.21 (Ar--C), 215.04 (C═O); ¹⁵ N NMR (DCCl₃) ppm 39.18[N(3)], 40.31 [N(7)]. Anal. Calcd. for C₁₇ H₂₃ ClN₂ O: C, 66.55; H,7.56. Found: 66.47; H, 7.52.

EXAMPLE XV 7-(4'-Chlorobenzyl)-3-isopropyl-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (6)

To a mixture of KOH pellets (85%, 1.72 g, 26.1 mmol) and the ketone (22,1.0 g, 3.26 mmol) in triethylene glycol (30 mL) was added hydrazine(95%, 0.44 g, 13.0 mmol) in one portion in a 150-mL, jacketed flaskequipped with a magnetic stirrer, a heating mantle, a standardcondenser, a lower take-off condenser with a N₂ inlet, and three glassstoppers. A heating temperature of 200°-210° C. for 4 h under N₂ wasproduced by boiling tetralin (bp 207° C.) in the jacket. Cooling of thesolution to RT was followed by the addition of chilled water (40 mL).Combined extracts of the resulting suspension (ether, 4×30 mL) werewashed with 10% NaOH (30 mL) and saturated NaCl (30 mL), dried (Na₂ SO₄,4 h), filtered and concentrated to a light yellow oil which displayed nocarbonyl stretch in the IR spectrum and was used without furtherpurification. Dissolution of the oil in ether (60 mL) at ˜5° C. (via icewater bath) was followed by the dropwise addition of a solution of HClO₄(60%, 0.68 g, 4.08 mmol) in (H₃ C)₂ CHOH (1 mL) over 5 min. Theresulting, precipitated solid was filtered and recrystallized (95% EtOH)to give 0.81 g (63.3%) of white crystals of (6); mp 140°-141° C. IR(KBr) cm⁻¹ 3060, 3020 (Ar C--H), 2970, 2920, 2830 (C--H), 1485 (C═C),1085 (Cl--O), 790 (C--H out of plane, para); ¹ H NMR (DMSO-d₆) δ1.19 (d,6H, CH₃, J=6.7 Hz), 1.61 [d, 1H, H(9), J=12.7 Hz], 1.82 [d, 1H, H(9),J=12.2 Hz], 2.14 [bs, 2H, H(1,5)], 2.41 [bd, 2H, H(6,8)_(ax), J=11.2Hz], 3.04 [bd, 2H, H(6,8)_(eq), J=11.1 Hz], 3.16 [bd, 2H, H(2,4)_(ax),J=11.2 Hz], 3.34 [bd, 2H, H(2,4)_(eq), J=11.7 Hz], 3.44-3.52 [m, 3H,CH(CH₃)₂ and ArCH₂ ], 7.44 [s, 4H, Ar--H]; ¹³ C NMR (DMSO-d₆) ppm 16.10(CH₃), 27.25 [C(1,5)], 29.60 [C(9)], 52.77 [C(2,4)], 56.25 [CH(CH₃)₂ ],56.75 [C(6,8)], 60.42 (ArCH₂), 128.28, 131.27, 132.14, 135.72 (Ar--C);¹⁵ N NMR (DMSO-d₆) ppm 50.34 [N(7)], 60.57 [N(3)] . Anal. Calcd. for C₁₇H₂₀ Cl₂ N₂ O₄ : C, 51.92; H, 6.66. Found: C, 51.74; H, 6.57.

EXAMPLE XVI3-(4'-Chlorobenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane (33)

A 25-mL, three-necked, round-bottomed flask was equipped with a magneticstirrer, a standard condenser with a N₂ inlet, a 10-mL addition funneland two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57mmol) in CH₂ Cl₂ (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was addeddropwise a solution of 4-chlorobenzoyl chloride (0.69 g, 3.92 mmol) inCH₂ Cl₂ (5 mL) over 15 min. Stirring of the mixture was continued for anadditional 3 h under N₂. An aqueous mixture, formed upon addition of H₂O (30 mL), was extracted (CH₂ Cl₂, 4×25 mL). Combined extracts weredried (Na₂ SO₄, 2 h), filtered, and concentrated to give a viscousyellow oil. Chromatography of the oil was performed by adding an ethersolution of the oil to a neutral alumina column (69 g, 1.7 cm×30 cm) andthen using 60:40 hexanes/ethyl acetate as eluant. Fractions (R_(f)=0.41) were saved and concentrated (rotary evaporator then vacuum pump,overnight, RT/0.2 mm Hg) to give 0.86 g (80.4%) of off-white solid (33);mp 97°-98° C. IR (KBr) cm⁻¹ 3085, 3070 (Ar C--H), 2965, 2935, 2865,2800, 2770 (C--H), 1630 (C═O); ¹ H NMR (DCCl₃) δ0.95 (d;, 3H, CH₃, J=6.5Hz), 1.05 (d, 3H, CH₃, J=6.4 Hz), 1.63-1.75 [m, 3H, H(5) and H(9)], 1.97[bs, 1H, H(1)], 2.41 [bd, 1H, H(4)_(ax), J=10.6 Hz], 2.50 [bd, 1H,H(6)_(ax), J=11.2H], 2.59 [heptet, 1H, CH(CH₃)₂, J=6.5 Hz] , 2.71 [bd,1H, H(6)_(eq), J=11.0 Hz], 3.03-3.06 [m, 2H, H(2)_(ax) and H(4)_(eq) ],3.31 [bd, 1H, H(8)_(ax), J=12.8 Hz], 3.71 [bd, 1H, H(8)_(eq), 13.1 Hz],4.77 [bd, 1H, H(2)_(eq), J=13.2 Hz], 7.27-7.37 (m, 4H, Ar--H); ¹³ C NMR(DCCl₃) ppm 16.37, 19.35 (CH₃), 29.07 [C(1)], 29.07 [C(1)], 29.80[C(5)], 32.29 [C(9)], 46.68 [C(2)], 52.22 [C(4)], 52.56 [C(8)], 54.38[CH(CH₃)₂ ], 54.79 [C(6)], 128.35, 128.51, 134.67, 136.11 (Ar-- C),169.03 (C═O). Anal. Calcd. for C₁₇ H₂₃ ClN₂ O: C, 66.55; H, 7.56. Found:C, 66.45; H, 7.71.

EXAMPLE XVII β,β'-Dibromoisobutyric Acid (46)

Into a 500-mL, single necked, round-bottomed flask equipped with aheating mantle, a magnetic stirrer, a Claisen distillation head, astandard condenser and a receiver were placed diethylbis(hydroxymethyl)malonate (45, 37 g, 0.17 mol), and hydrobromic acid(48%, 280 mL, 2.5 mol). The resulting homogeneous solution was distilledfor 2.5 h (35°-126° C.), and 100 mL of distillate was collected. Heatingwas momentarily stopped, and the distillation head, condenser andreceiver were removed and replaced with a condenser. The mixture washeated at reflux for 6 h. A brown reaction mixture was poured into a 250mL Erlenmeyer flask which was allowed to cool to RT (1 h) and then wasplaced in an ice bath (1 h) to yield acid (46) as a white solid. Thiswhite solid was filtered off using a Buchner funnel under suction(aspirator) and was then washed with cold H₂ O (50 mL) to afford, afterdrying (Abderhalden, 78° C., 12 h/0.2 mm Hg, P₂ O₅), acid (19.1 g,46.3%); mp 96°-97° C. The mother liquor was concentrated to about 75 mLand then cooled to RT (0.5 h) [followed by an ice bath (0.5 h)] to yielda second crop of the acid (46) (3.7 g, 9.0%); mp 95°-97° C. IR (KBr)cm⁻¹ 3500-2500 (CO₂ H), 1700 (C═O); ¹ H NMR (DCCl₃) δ3.27 (m, 1H, CH),3.79 (m, 4H, CH₂ Br), 10.91 (bs, 1H, CO₂ H); ¹³ C NMR (DCCl₃) ppm 29.80(t, CH₂ Br), 48.38 (d, CH), 175.30 (s, CO₂ H).

EXAMPLE XVIII Ethyl β,β'-Dibromoisobutyrate (47)

Into a 250-mL, single necked, round-bottomed flask equipped with asoxhlet extractor, standard condenser, magnetic stirrer and heatingmantle were placed the dibromo acid (46, 27 g, 0.11 mol), benzene (125mL), absolute ethanol (50 mL) and conc H₂ SO₄ (0.5 mL). Into the Soxhletextractor was placed a thimble containing anhydrous MgSO₄ (20 g). Thereaction mixture was heated at reflux for 24 h. Solvent was distilledoff until about 50 mL remained. The concentrated reaction mixture wascooled to RT (0.5 h), and H₂ O (50 mL) was added followed by slowaddition of solid NaHCO₃ with stirring until the pH was 7. The resultingsuspension was transferred to a separatory funnel and the organic layerwas separated. The aqueous layer was extracted with ether (3×50 mL). Theorganic layers were combined and washed with H₂ O (50 mL) and saturatedNaCl (50 mL). This was followed by drying (anhydrous MgSO₄, 2 h),filtration, and evaporation (rotary evaporator, aspirator) to yield apale brown liquid which was distilled under reduced pressure to yieldthe ester (47,.3 g, 94.9%), bp 60°-62° C./0.2 mm Hg. IR (film) cm⁻¹ 1735(C═O); ¹ H NMR (DCCl₃) δ1.30 (t, 3H, CH₃), 3.20 (m, 1H, CH), 3.78 (m,4H, CH₂ Br), 4.25 (q, 2H, OCH₂); ¹³ C NMR (DCCl₃) ppm 14.18 (q, CH₃),30.75 (t, CH₂ Br), 48.52 (d, CH), 61.66 (t, OCH₂), 169.32 (s, CO₂ Et).

EXAMPLE XIX Ethyl3-Benzyl-3-azabicyclo[3.3.1]nonan-9-one-7-(endo)-carboxylate (20)

As the starting point for the preparation of (20), the preparation of1-benzyl-4-pyrrolidinyl-1,2,3,6-tetrahydropyridine was required. Into a250-mL, single-necked, round-bottomed flask equipped with a Dean-Starktrap, standard condenser, magnetic stirrer, heating mantle, and a N₂inlet were placed 1-benzyl-4-piperidinone (43, 10.2 g, 55 mmol), benzene(125 mL) and pyrrolidine (6.0 g, 85 mmol). The resulting mixture washeated at reflux for 24 h. The Dean-Stark trap was removed and a simpledistillation apparatus was installed. Distillation of the solvent wascompleted at atmospheric pressure followed by another distillation underreduced pressure to yield the enamine as a pale yellow oil (12.7 g,97.0%), bp 167°-169° C./0.2 mm Hg. IR (film) cm⁻¹ 1650 (C═C--N); ¹ H NMR(DCCl₃) δ1.79 [bs, 4H, H(9,10)], 2.30 [bs, 2H, H(3)], 2.56 [t, 2H,H(2)], 3.00 [bs, 2H, H(8,11)], 3.05 [bs, 2H, H(6)], 3.54 (s, 2H, CH₂Ph), 4.16 [bs, 1H, H(5)], 7.26-7.33 (m, 5H, Ar--H); ¹³ C NMR (DCCl₃) ppm24.69 [t, C(9,10)], 28.31 [t, C(3)], 47.10 [t, C(8,11)], 50.07 [t,C(2)], 52.94 [t, C(6)], 62.68 (t, CH₂ Ph), 90.24 [d, C(5)], 126.64,127.88, 128.92, 138.61 (Ar--C), 141.29 [s, C(4)].

Into a 250-mL, three-necked, round-bottomed flask equipped with aheating mantle, magnetic stirrer, standard condenser, dropping funneland a N₂ inlet were placed a solution of the above enamine [9.9 g, 40mmol in CH₃ CN (50 mL)] and triethylamine (11.6 g, 9.1 g, 90 mmol). Theresulting mixture was heated at reflux, and, to the boiling solution wasadded dropwise a solution of the dibromo ester (47, 11.1 g, 40 mmol) inCH₃ CN (20 mL) over a period of 0.5 h. During addition, triethylammoniumbromide precipitated as a white solid, and the reaction mixture turnedbrown. Heating was continued for 3.5 h after the addition was complete.Solvent was removed (rotary evaporator) to yield a dark brown oil towhich was added H₂ O (50 mL). The mixture was extracted with HCCl₃ (4×50mL). The organic layers were combined and washed successively with HCl(1N, 2×50 mL), NaHCO₃ (saturated aqueous, 2× 50 mL) and NaCl (saturated,2×50 mL). After drying (anhydrous Na₂ SO₄), the solution was filteredand evaporated (rotary evaporator) to yield the crude ketone (20) as adark brown oil. This dark brown oil was purified by columnchromotography over silica gel (150 g, 3.8 cm×61 cm; 1 mL/min) using 10%EtOAc in hexanes as the eluant to yield ketone (20) as a pale yellow,viscous oil (4.1 g, 33.0%). R_(f) =0.49 in 9:1 hexanes:EtOAc. IR (film)cm⁻¹ 1730 (C═O); ¹ H NMR (DCCl₃) δ1.30 (t, 3H, CH₃), 2.18 [dd, 2H,H(6,8)_(ax), J=6.9, 15.9 Hz], 2.29 [bs, 2H, H(1,5)], 2.44 [m, 3H,H(6,8)_(eq) and H(7)_(exo) ], 2.82 [dd, 2H, H(2,4)_(ax), J=6.0, 14.4Hz], 3.04 [d, 2H, H(2,4)_(eq), J=10.6 Hz], 3.56 (s, 2H, CH₂ Ph), 4.22(q, 2H, OCH₂), 7.17-7.30 (m, 5H, Ar--H); ¹³ C NMR (DCCl₃) ppm 14.35 (q,CH₃), 33.21 [t, C(6,8)], 37.75 [d, C(7)], 46.61 [d, C(1,5)], 58.06 (t,CH₂ Ph), 60.34 (t, OCH₂), 127.26, 128.09, 129.50, 135.10 (Ar--C), 172.40(s, CO₂ Et), 215.92 (C═O). The oil, very slightly crude (20), was usedwithout further purification for succeeding steps since the oildecomposed upon attempted distillation.

EXAMPLE XX Ethyl3-Benzyl-9,9-(1,3-dithiolan-2-yl)-3-azabicyclo[3.3.1]nonane-7-(endo)-carboxylate(38)

Into a 100-mL, three-necked, round-bottomed flask equipped with amagnetic stirrer, standard condenser, dropping funnel, N₂ inlet and anice-bath were placed the ketone (20, 3.01 g, 10 mmol), 1,2-ethanedithiol(2 mL, 2.25 g, 24 mmol), and dry HCCl₃ (50 mL). The resulting mixturewas cooled to 0°-5° C. in an ice bath. Freshly distilled BF₃ etherate (4mL, 2.2 g, 15 mmol) was added dropwise over a period of 0.5 h. Thereaction mixture was stirred at 0°-5° C. for 1 h and then at RT for 8 h.To the resulting mixture was added HCCl₃ (25 mL), and the solution wassuccessively washed with NaOH (1N, 3×50 mL) and NaCl (saturated, 50 mL).After drying (anhydrous Na₂ SO₄), the solution was filtered andevaporated (rotary evaporator, aspirator) to yield the crude thioketal(38) as a pale yellow, viscous oil, which was purified by columnchromatography over silica gel (105 g) using 10% EtOAc in hexanes as theeluant. The thioketal was obtained as a colorless oil which crystallizedout as a white solid upon standing at RT (12 h). This white solid wasrecrystallized (hexanes) to yield solid thioketal (38) as white needles(1.6 g, 42.0%, mp 76°-78° C.). IR (KBr) cm⁻¹ 1715 (CO₂ Et); ¹ H NMR(DCCl₃) δ1.30 (t, 3H, CH₃), 1.90 [bs, 2H, H(1,5)], 2.34 [bd, 2H,H(6,8)_(ax) ], 2.47 [m, 1H, H(7)], 2.68-2.83 [m, 6H, H(6,8)_(eq),H(2,4)_(ax) and H(2,4)_(eq) ], 3.10-3.17 (m, 4H, SCH₂), 3.44 (s, 2H, CH₂Ph), 4.19 (q, 2H, OCH₂ ), 7.12-7.33 (m, 5H, Ar--H); ¹³ C NMR (DCCl₃) ppm14.36 (q, CH₃), 30.25 [t, C(6,8)], 36.71 [d, C(7)], 38.21, 38.64 (t,SCH₂), 42.10 [d, C(1,5)], 54.92 [t, C(2,4)], 60.14 (t, CH₂ Ph), 60.27(t, OCH₂), 127.00, 127.84, 129.91, 134.21 (Ar--C), 172.35 (CO₂ Et).Anal. Calcd. for C₂₀ H₂₇ NO₂ S₂ : C, 63.66; H, 7.16; S, 16.97. Found: C,63.99; H, 7.08; S, 17.23.

EXAMPLE XXI Ethyl3-Benzyl-9,9-(1,3-dithiolan-2-yl)-3-azabicyclo[3.3.1]nonane-7-(endo)-carboxylateHydroperchlorate (14)

Into a 250-mL Erlenmeyer flask equipped with a magnetic stirrer wereplaced the thioketal (38, 1.5 g, 4 mmol), anhydrous ether (150 mL), andabsolute ethanol (5 mL). The resulting solution was cooled in an icebath for 0.5 h. To this cooled solution was added dropwise HClO₄ (60%,0.85 g, 5 mmol) over a period of 0.5 h. During the addition a whitesolid precipitated. The resulting mixture was stirred in an ice bath foranother 1 h, after the addition was complete, and then for 2 h at RT.The white solid obtained by filtration was recrystallized (isopropylalcohol) to yield the thioketal hydroperchlorate (14) as white needles(1.7 g, 90.0%); mp 153°-154° C. IR (KBr) cm⁻¹ 3400 (N--H), 1700 (CO₂Et), 1100 (Cl--O); ¹ H NMR (DCCl₃) δ1.30 (t, 3H, CH₃), 2.05 [d, 2 H,H(6,8)_(ax), J=16.1 Hz], 2.36 [bs, 2H, H(1,5)], 2.71 [m, 2H, H(6,8)_(eq)], 3.33 (m, 4H, SCH₂), 3.50 [m, 2H, H(2,4)_(ax) ], 3.68 (d, 2H, CH₂ Ph),7.43-7.60 (m, 5H, Ar--H), 10.30 (bs, 1H, N--H); ¹³ C NMR (DCCl₃) ppm13.79 (q, CH₃), 28.42 [t, C(6,8)], 29.53 [d, C(7)], 39.18 [d, C(1,5)],39.51, 39.88 (t, SCH₂), 56.60 [t, C(2,4)], 61.81 (t, CH₂ Ph), 63.67 (t,OCH₂), 68.96 [s, C(9)], 127.84, 129.93, 130.31, 131.57 (Ar--C), 183.05(s, CO₂ Et). Anal. Calcd. for C₂₀ H₂₈ ClNO₆ S₂ : C, 50.26; H, 5.86; N,2.93. Found: C, 50.24; H, 6.12; N, 2.94.

EXAMPLE XXII Ethyl3-Benzyl-3-azabicyclo[3.3.1]nonane-7-(endo)-carboxylate Hydroperchlorate(13)

Ester (38) (1.89 g, 0.005 mol), ethanol (200 mL), and Raney nickel(about 20 mL of a wet solid) were heated together at reflux for 18hours, and the mixture was allowed to cool. After the mixture wasfiltered, the solvent was evaporated to a viscous oil. The oil wastreated with a saturated brine solution, and the resulting mixture wasextracted with chloroform (3×50 mL). Evaporation of the solvent gave acolorless oil (0.97 g, 68.0%). Thus, slightly crude ethyl3-benzyl-3-azabicyclo[3.3.1]nonane-7-(endo)-carboxylate was used in thenext step without further purification.

Into a 250 mL Erlenmeyer flask equipped with magnetic stirrer wereplaced the above ester (0.95 g, 3 mmol), anhydrous ether (150 mL), andabsolute ethanol (5 mL). The resulting solution was cooled in ice bathand to the chilled solution was added dropwise HClO₄ (60%, 0.75 g, 4.5mmol) over a period of 0.5 h. During the addition, a white solidprecipitated. The resulting mixture was stirred in ice bath for 1 h,after the addition was complete, and then for 2 h at RT. Filtration andrecrystallization (isopropyl alcohol) yielded the hydroperchlorate (13)as colorless platelets (0.87 g, 68.0%); mp 130°-131° C. IR (KBr) cm⁻¹3440 (N--H), 1700 (CO₂ Et), 1100 (Cl--O); ¹ H NMR (DCCl₃) δ1.30 (t, 3H,CH₃), 1.61 [bd, 1H, H(9)_(endo) ], 1.87 [d, 2H, H(6,8)_(ax), J=12 Hz],2.05 [bd, 1H, H(9)_(exo) ], 2.16-2.31 [m, 4H, H(1,5) and H(6,8)_(eq) ],2.91-2.98 [m, 1H, H(7)], 3.35-3.48 [m, 4H, H(2,4)_(ax) and H(2,4)_(eq)], 4.32 (q, 2H, OCH₂), 4.50 (d, 2H, CH₂ Ph), 7.38-7.68 (m, 5H, Ar--H);¹³ C NMR (DCCl₃) ppm 13.79 (q, CH₃), 25.74 [d, C(1,5)], 27.85 [t,C(6,8)], 31.91 [d, C(7)], 55.96 [t, C(2,4)], 61.68 (t, CH₂ Ph), 63.05(t, OCH₂), 128.60, 129.98, 131.25, (Ar--C), 182.93 (s, CO₂ Et). Anal.Calcd. for C₁₈ H₂₆ ClNO₆ : C, 55.75; H, 6.71. Found: C, 56.11; H, 6.82.

EXAMPLE XXIII7-Isopropyl-3-(3',4',5'-trimethoxybenzoyl)-3,7-diazabicyclo[3.3.1]nonane(35)

A 25-mL, three-necked, round-bottomed flask was equipped with a magneticstirrer, a standard condenser with N₂ inlet, a 10-mL addition funnel andtwo glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) inCH₂ Cl₂ (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise asolution of 3,4,5-trimethoxybenzoyl chloride (0.92 g, 3.92 mmol) in CH₂Cl₂ (5 mL) over 15 min. Stirring of the mixture was continued for anadditional 3 h under N₂. An aqueous mixture, upon addition of H₂ O (30mL), was extracted (CH₂ Cl₂, 4×25 mL). Combined extracts were dried (Na₂SO₄, 2 h), filtered, and concentrated to give a viscous yellow oil.Chromatography of the oil was performed on neutral alumina (74 g, 1.7cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (R_(f)=0.34) were saved and concentrated (rotary evaporator then vacuum pump,overnight, RT/0.2 mm Hg) to give 1.02 g (79.1%) of off-white solid (35);mp 67.5°-69.5° C. IR (KBr) cm⁻¹ 3055 (Ar C--H), 2985, 2955, 2910, 2890,2780 (C--H), 1620 (C═O); ¹ H NMR (DCCl₃) δ0.96 (d, 3H, CH₃, J=6.5 Hz),1.09 (d, 3H, CH₃, J=6.7 Hz), 1.64-1.79 [m, 3H, H(5) and H(9)], 2.05 [bs,1H, H(1)], 2.44 [bd, 1H, H(4)_(ax), J=10.6 Hz], 2.57 [bd, 1H, H(6)_(ax),J=10.8 Hz], 2.66 [heptet, 1H, CH(CH₃)₂, J=6.6 Hz], 2.71 [bd, 1H,H(6)_(eq), J=11.0 Hz], 3.02-3.07 [m, 2H, H(4)_(eq) and H(2)_(ax) ], 3.31[bd, 1H, H(8)_(ax), J=13.2 Hz], 3.80-3.92 [m, 10H, H(8)_(eq) and OCH₃ ],4.77 [bd, 1H, H(2)_(eq), J=13.5 Hz], 7.29 (s, 2H, Ar--H); ¹³ C NMR(DCCl₃) ppm 15.87, 19.42 (CH₃), 29.02 [C(1)], 29.78 [C(5)], 32.35[C(9)], 46.64 [C(2)], 51.73 [C(4)], 52.48 [C(8)], 54.39 [CH(CH₃)₂ ],54.95 [C(6)], 56.13, 60.86 (OCH₃), 103.83, 133.32, 133.21, 138.22,153.21 (Ar--C), 169.66 (C═O). Anal. Calcd. for C₂₀ H₃₀ N.sub. 2 O₄ : C,66.27; H, 8.34. Found: C, 66.04; H, 8.32.

EXAMPLE XXIV

3-(3',4'-Dimethoxybenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane(34)

A 25-mL, three-necked, round-bottomed flask was equipped with a magneticstirrer, a standard condenser with a N₂ inlet, a 10-mL addition funnel,and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57mmol) in CH₂ Cl₂ (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was addeddropwise a solution of 3,4-dimethoxybenzoyl chloride (0.80 g, 3.92 mmol)in CH₂ Cl₂ (10 mL) over 15 min. Stirring of the mixture was continuedfor an additional 3 h under N₂. An aqueous mixture, formed upon additionof H₂ O (30 mL), was extracted (CH₂ Cl₂, 4×25 mL). Combined extractswere dried (Na₂ SO₄, 2 h), filtered and concentrated to give a viscousyellow oil. Chromatography of the oil was performed on neutral alumina(74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant.Fractions (R_(f) = 0.31) were saved and concentrated (rotary evaporatorthen vacuum pump, overnight, RT/0.2 mm Hg) to give 0.87 g (73.1%) ofoff-white solid (34); mp 67.5°-69.5° C. IR (KBr) cm⁻¹ 3055 (Ar C--H),2950, 2915, 2845, 2820, 2770, 2750, 2710 (C--H), 1625 (C═O); ¹ H NMR(DCCl₃) δ0.96 (d, 3H, CH₃, J=6.4 Hz), 1.06 (d, 3H, CH₃, J=6.5 Hz),1.62-1.75 [m, 3H, H(5) and H(9)], 1.96 [bs, 1H, H(1)], 2.43 [bd, 1H,H(4)_(ax), J=9.7 Hz], 2.51 [bd, 1H, H(6)_(ax), J=10.5 Hz], 2.62 [heptet,1H, CH(CH₃)₂, J=6.4 Hz], 2.74 [bd, 1H, H(6)_(eq), J=9.9 Hz], 3.00-3.09[m, 2H, H(4)_(eq) and H(2)_(ax) ], 3.32 [bd, 1H, H(8)_(ax), J=13.2 Hz],3.83-3.94 [m, 7H, H(8)_(eq) and OCH₃ ], 4.77 [bd, 1H, H(2)_(eq), J=13.3Hz], 6.84-6.94 (m, 3H, Ar--H); ¹³ C NMR (DCCl₃) ppm 16.46, 19.15 (CH₃),29.13 [C(1)], 29.86 [C(5)], 32.36 [C(9)], 46.71 [C(2)], 52.25 [C(4)],52.65 [C(8)], 54.35 [CH(CH₃)₂ ], 54.68 [C(6)], 55.88, 55.93 (OCH₃),110.50, 119.64, 130.23, 148.78, 149.39 (Ar--C), 169.90 (C═O). Anal.Calcd. for C₁₉ H₂₈ N₂ O₃ : C, 68.65; H, 8.49. Found: C, 68.58; H, 8.47.

EXAMPLE XXV3-(3',4'-Dimethoxybenzoyl)-7-isopropyl-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (3)

A 50-mL Erlenmeyer flask was equipped with a magnetic stirrer and an icebath. To a chilled (5° C.), stirred solution of the amide (34, 0.30 g,0.90 mmol) in ether (30 mL) was added dropwise a solution of HClO₄ (60%,0.18 g, 1.08 mmol) in isopropyl alcohol (1 mL) over 10 min. A whiteprecipitate resulted which was filtered and then stirred in hot CH₃ OH(10 mL) for 20 min. The mixture was filtered and dried (Abderhalden, P₂O₅, overnight, RT/0.2 mm Hg) to give 0.27 g (69.2%) of white solid (3);mp 235°-236° C. (dec). IR (KBr) cm⁻¹ 3130 (N--H), 3010 (Ar C--H), 2975,2945, 2920 (C--H), 1635 (C═O), 1095 (Cl--O); ¹ H NMR (DMSO-d₆, 80° C.)δ1.33 (d, 6H, CH₃, J= 6.7 Hz), 1.74 [bd, 1H, H(9), J=12.8 Hz], 1.91 [bd,1H, H(9), J=13.2 Hz], 2.27 [bs, 2H, H(1,5)], 3.12 [bd, 2H, H(6,8)_(ax),J=13.7 Hz], 3.19-3.28 [m, 2H, H(2,4)_(ax) ], 3.42-3.56 [m, 3H,H(6,8)_(eq) and CH(CH₃)₂ ], 3.78, 3.81 (two s, 6H, OCH₃), 3.97 [bd, 2H,H(2,4)_(eq), J=13.6 Hz], 6.94-7.03 [m, 3H, Ar--H], 7.81 (bs, 1H, N--H);¹³ C NMR (DMSO-d₆, 80° C.) ppm 16.34 (CH₃), 26.81 [C(1,5)], 27.80[C(9)], 49.06 [C(2,4)], 52.40 [ C(6,8)], 55.88, 55.92 (OCH₃), 59.97[CH(CH₃)₂ ], 111.85, 112.10, 120.44, 128.68, 148.74, 150.26 (Ar--C),172.97 (C═O). Anal. Calcd. for C₁₉ H₂₉ ClN₂ O₇ : C, 52.72; H, 6.75.Found: C, 52.35; H, 6.77.

EXAMPLE XXVI 3-Benzenesulfonyl-7-isopropyl-3,7-diazabicyclo[3.3.1]nonane(36)

A 50-mL, three-necked, round-bottomed flask was equipped with a magneticstirrer, a standard condenser with a N₂ inlet, an ice bath, a 10-mLaddition funnel, and a glass stopper. To a stirred, ice cold (5° C.)mixture of the amine (31, 1.03 g, 6.12 mmol) and NaOH pellets (97%, 0.76g, 18.4 mmol) in H₂ O (7 mL) and CH₂ Cl₂ (5 mL) was added dropwise asolution of benzenesulfonyl chloride (2.16 g, 12.2 mmol) in CH₂ Cl₂ (5mL) over 30 min. Stirring of the mixture was continued for an additional17.5 h at RT. The reaction mixture was then partioned between H₂ O (30mL) and CH₂ Cl₂ (30 mL) followed by basification (pH˜12) of the aqueousphase. Extracts (CH₂ Cl₂,3×30 mL) of the remaining water layer werecombined with the initial organic layer. The solution was washed with10% NaOH (30mL) and then saturated NaCl (30 mL); it was dried (Na₂ SO₄,overnight), filtered, and concentrated to give an orange viscous oil.Chromatography of the oil was performed on silica gel (39 g, 1.6 cm×62cm) using 10% CH₃ OH/CH₂ Cl₂. Fractions (R_(f) =0.44) were saved,concentrated, and reeluted on neutral alumina (90 g, 2.5 cm×18 cm)employing ethyl acetate as eluant. Fractions (R_(f) =0.53) were savedand concentrated. A colored impurity persisted which was removed byagain eluting over silica gel (21 g, 1.6 cm×33 cm) using 5% CH₃ OH/CH₂Cl₂ as eluant. Fractions (R_(f) =0.34) were combined and concentrated(rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give0.54 g (28.6%) of white solid (36); mp 85.5°-86.5° C. IR (KBr) cm⁻¹ 3060(Ar C--H), 2960, 2910, 2890, 2865, 2820 (C--H), 1585 (C═C), 1340, 1170(S═O), 760, 720 (C--H out of plane, mono); ¹ H NMR (DMSO-d₆) δ0.88 (d,6H, CH₃, J=6.5 Hz), 1.40 [bs, 2H, H(9)], 1.94 [bs, 2H, H(1,5)], 2.35[bd, 2H, H(6,8)_(ax), J=10.3 Hz], 2.53 [heptet, 1H, CH(CH₃)₂, J=6.5 Hz],2.69 [bd, 2H, H(6,8)_(eq), J=10.3 Hz], 2.89 [dd, 2H, H(2,4)_(ax), J=11.2Hz, J'=4.5 Hz], 3.36 [d, 2H, H(2,4)_(eq), J=10.9 Hz], 7.58-7.75 (m, 5H,Ar--H); ¹³ C NMR (DMSO-d₆) ppm 17.57 (CH₃), 27.39 [C(1,5)], 28.95[C(9)], 48.88 [C(2,4)], 52.66[C(6,8)], 53.42 [CH(CH₃)₂ ], 126.90,129.01, 132.36, 136.79 (Ar--C). Anal. Calcd. for C₁₆ H₂₄ N₂ O₂ S: C,62.31; H, 7.85. Found: C, 62.48; H, 7.69.

EXAMPLE XXVII 7-Isopropyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (26)

A three-necked, 300-mL, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a standard condenser with a N₂inlet, and two glass stoppers. A mixture containing isopropylamine (2.96g, 50 mmol), paraformaldehyde (12.01 g, 400 mmol), and CH₃ OH(188 mL)was made acidic with glacial acetic acid (4.5 g, 75 mmol). In oneportion, 4-thianone (44, 5.81 g, 50 mmol) was added followed by stirringat reflux for 21 h. Evaporation of the solvent gave a red oil, which wasdiluted with H₂ O (200 mL) and extracted with ether (2×100 mL), thelatter being discarded. Basification (pH˜12) of the aqueous layer by theaddition of NaOH pellets (3.0 g, 75 mmol) resulted in the formation of ayellow suspension which was extracted with CH₂ Cl₂ (4×100 mL). Combinedextracts were dried (MgSO₄, overnight), filtered, and concentrated toafford a yellow oil which solidified upon standing. This solid wasdigested in 250 mL of Skelly B (bp 60°-68° C.) for 30 min, and thesupernatant was decanted. Evaporation of the solvent, followed byheating the crude solid in vacuo (95°-110° C./0.3 mm Hg) in asublimation apparatus gave a sticky white solid (mp 54°-57° C.).Recrystallization (Skelly B) afforded 4.15 g (41.6%) of white flakes ofketone (26); mp 59°-60° C. IR (KBr) cm⁻¹ 2965, 2935, 2900, 2875, 2805(C--H), 1730 (C═O); ¹ H NMR (DCCl₃) δ1.04 (d, 6H, CH₃, J=6.7 Hz),2.75-2.90 [m, 5H, ring protons, CH(CH₃)₂, and H(1,5)], 3.05-3.13 (m, 4H,ring protons), 3.24-3.29 (m, 2H, ring protons); ¹³ C NMR (DCCl₃) ppm18.30 (q, CH₃), 34.16 [t, C(2,4)], 47.52 [d, C(1,5)], 53.76 [d, CH(CH₃)₂], 54.16 [t, C(6,8)], 213.68 (s, C═O); ¹⁵ N NMR (DCCl₃) ppm 39.27[N(7)]. Anal. Calcd. for C₁₀ H₁₇ NOS: C, 60.26; H, 8.60. Found: C,60.40; H, 8.65.

EXAMPLE XXVIII 7-Isopropyl-3-thia-7-azabicyclo[3.3.1]nonaneHydroperchlorate (8)

To a mixture of KOH pellets (85%, 3.96 g, 60 mmol) and the ketone (26,1.0 g, 5 mmol) in triethylene glycol (25 mL) was added hydrazine (95%,1.69 g, 50 mmol) in one portion in a 70 mL, jacketed flask equipped witha magnetic stirrer, a heating mantle, a standard condenser, a lowertake-off condenser with a N₂ inlet, and two glass stoppers. A heatingtemperature of 200°-210° C. for 5 h was produced by boiling tetralin (bp207° C.) in the jacket. After cooling to RT, the solution was dilutedwith chilled water (100 mL) and extracted with ether (4×50 mL). Combinedextracts were washed with 10% NaOH (50 mL) and saturated NaCl (50 mL),dried (Na₂ SO₄, overnight), filtered, and concentrated to a yellow oil(0.8 g). Dissolution of the oil in ether (50 mL) via magnetic stirringand cooling (5° C.) with an external ice bath was followed by dropwiseaddition of a solution of HClO₄ (60%, 1.08 g, 6.45 mmol) in isopropylalcohol (3 mL) over 10 min. Stirring of the mixture an additional 10min, filtering the precipitated salt, and then washing the latter withether (˜50 mL) gave an off-white solid. Dissolving the salt in hot 95%EtOH and decolorizing the solution with Norit, followed by filtering,and cooling, afforded 0.91 g (63.6%) of salt (8) as a white solid; mp281°-282.5° C. IR (KBr) cm⁻¹ 3060 (N--H), 3000, 2960, 2935 (C--H), 1090(Cl--O); ¹ H NMR (DMSO-d₆) δ1.28 (d, 6H, CH₃), 1.76 [d, 1H, H(9), J=13.3Hz], 1.91 [d, 1H, H(9), J=12.9 Hz], 2.35 [bs, 2H, H(1,5)], 2.78 [bd, 2H,H(2,4)_(ax), J=12.2 Hz], 3.14 [bd, 2H, H(2,4)_(eq), J=13.6 Hz],3.29-3.57 [m, 3H, H(6,8)_(ax) and CH(CH₃)₂ ], 3.62 [d, 2H, H(6,8)_(eq),J=12.7 Hz], 9.07 (bs, 1H, N--H); ¹³ C NMR (DMSO-d₆) ppm 16.19 (q, CH₃),25.51 [d, C(1,5)], 28.35 [t, C(9)], 30.69 [t, C(2,4)], 52.36 [t,C(6,8)], 58.66 [d, CH(CH₃)₂ ]; ¹⁵ N NMR (DMSO-d₆) ppm 58.47 [N(7)].Anal. Calcd. for C₁₀ H₂₀ ClNO₄ S: C, 42.03; H, 7.05. Found: C, 42.10; H,7.18.

EXAMPLE XXIX 7-(3'-Iodobenzyl)-3-thia-7-azabicyclo[3.3.1]nonan-9-one(25)

A 100 mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a standard condenser with a N₂inlet, and two glass stoppers. A mixture containing 3-iodobenzylamine(1.19 g, 5.10 mmol), paraformaldehyde (1.22 g, 40.8 mmol), and CH₃ OH(30 mL) was made acidic with glacial acetic acid (0.46 g, 7.65 mmol). Inone portion, 4-thianone (44, 0.59 g, 5.10 mmol) was added and theresulting mixture was heated under N₂ at reflux for 21 h. Evaporation ofthe solvent gave a reddish oil, which was dissolved in H₂ O (40 mL).Basification (pH˜13) of the solution by the dropwise addition of 10%NaOH resulted in the formation of a milky suspension which was extractedwith ether (5×40 mL). Combined extracts were dried (Na₂ SO₄, overnight),filtered, and concentrated to a yellow oil. Digestion of the oiloccurred in Skelly B (125 mL, bp 60°-68° C.) for 30 min, and thesupernatant was decanted. Further digestion of the residual material waseffected in pentane (2×125 mL) for 30 min. Combined supernatant extractswere concentrated (rotary evaporator the vacuum pump, overnight, RT/0.2mm Hg) to give 0.84 g (57.5%) of a slightly crude viscous oil (25) whichwas used without further purification in the next step. IR (film) cm⁻¹3055 (Ar C--H), 2930, 2825 (C--H), 1735 (C═O), 885, 790, 695 (C--H outof plane, meta); ¹ H NMR (DCCl₃) δ2.72-3.18 [m, 10H, ring protons andH(1,5)], 3.51 (s, 2H, ArCH₂), 7.07-7.71 (m, 4H, Ar--H); ¹³ C NMR (DCCl₃)ppm 35.05 [C(2,4)], 46.95 [C(1,5)], 58.20 [C(6,8)], 60.69 (ArCH₂),94.43, 127.98, 130.23, 136.44, 137.64, 140.63 (Ar--C), 213.00 (C═O).

EXAMPLE XXX 7-(3'-Iodobenzyl)-3-thia-7-azabicyclo[3.3.1]nonaneHydroperchlorate (9)

To a mixture of KOH pellets (85%, 0.48 g, 7.2 mmol) and the ketone (25,0.224 g, 0.60 mmol) in triethylene glycol (10 mL) was added hydrazine(95%, 0.20 g, 6.0 mmol) in one portion in a 50-mL, jacketed flaskequipped with a magnetic stirrer, a heating mantle, a standardcondenser, a lower take-off condenser with a N₂ inlet, and two glassstoppers. A heating temperature of 140°-150° C. for 4 h was produced byboiling o-xylene (bp 144° C.) in the jacket. After cooling to RT, thesolution was diluted with cold H₂ O (30 mL) and was then extracted withether (4×30 mL). Combined extracts were washed with 10% NaOH (30 mL) andsaturated NaCl (30 mL), dried (Na₂ SO₄, overnight), filtered, andconcentrated to give a yellow oil (209 mg). Dissolution in ether (25 mL)via magnetic stirring and cooling (5° C.) in a 50-mL Erlenmeyer flaskequipped with an external ice bath was followed by the dropwise additionof a solution of HClO₄ (60%, 0.15 g, 0.87 mmol) in isopropyl alcohol (1mL) over 10 min. Filtration of the precipitate and then washing thelatter with ether (˜50 mL) gave a solid which changed to an oil. Thisoil was dissolved in 95% EtOH, and the solution was decolorized withNorit, filtered, and left to stand at RT overnight. White crystallinesalt (9) was collected (77 mg, 27.7%); mp 169.5°-170° C. IR (KBr) cm⁻¹3045 (Ar C--H), 2950, 2915, 2825 (C--H), 1570 (C═C), 1085 (Cl--O), 780,765 (C--H) out of plane, meta); ¹ H NMR (DMSO-d₆) δ1.81 [m, 2H, H(9)],2.36 [bs, 2H, H(1,5)], 2.70 [d, 2H, H(2,4).sub. ax, J=13.6 Hz], 3.09 [d,2H, H(2,4)_(eq), J=13.7 Hz], 3.35 [m, 2H, H(6,8)_(ax) ], 3.58 [d, 2H,H(6,8)_(eq), J=11.9 Hz], 4.22 (s, 2H, ArCH₂), 4.24 (s, 1H, ArCH₂),7.32-8.03 (m, 4H, Ar--H), 9.20 (bs, 1H, N--H); ¹³ C NMR (DMSO-d₆) ppm25.78 [C(1,5)], 28.48 [C(9)], 30.65, [C(2,4)], 56.53 [C(6,8)], 60.04(ArCH₂), 95.40, 129.93, 131.08, 132.47, 138.18, 138.93 (Ar--C); ¹⁵ N NMR(DMSO-d₆) ppm 54.17 [N(7)]. Anal. Calcd. for C₁₄ H₁₉ ClINO₄ S: C, 36.58;H, 4.17; N, 3.05; I, 27.60. Found: C, 36.87; H, 4.15; N, 2.99; I, 27.64.

EXAMPLE XXXI 3,7-Dibenzyl-3,7-diazabicyclo[3.3.1]nonan-2-one (19)

A 500-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a heating mantle, a standard condenser with a N₂inlet, a 250-mL addition funnel, and a glass stopper. A mixture ofbenzylamine (10.71 g, 100 mmol), HCl (37%, 4.93 g, 50 mmol), glacialacetic acid (6.0 g, 100 mmol) and paraformaldehyde (6.31 g, 210 mmol) inCH₃ OH (100 mL) was brought to gentle reflux with stirring under N₂ over15 min. A solution of 1-benzyl-4-piperidinone (43, 18.93 g, 100 mmol)and glacial acetic acid (6.01 g, 100 mmol) in CH₃ OH (100 mL) was thenadded dropwise over 1 h and this was followed by a period of reflux foran additional 18 h. Upon cooling the mixture to RT, the solvent wasremoved and the resulting red oil was redissolved in H₂ O (100 mL).Combined extracts (ether, 2×100 mL) of the acidic aqueous layer werediscarded. Basification of the chilled (10° C., ice water bath) waterlayer to pH˜12 was effected by the addition of 10% NaOH. Combinedextracts (ether, 4×60 mL) were dried (Na₂ SO₄, 1 h), filtered, andconcentrated to give a viscous red oil. This oil was digested (Skelly B,2×250 mL, 20 min), and the supernatant extracts were concentrated andthen distilled (190°-215° C./10⁻⁵ mm Hg) to give an oil. Crystallizationof the oil was induced by dissolving the oil in hot pentane (800 mL) andthen chilling (-10° C.) the solution to give 14.66 g (45.8%) of white,crystalline ketone (19); mp 82.5°-83.5° C. Concentration (hot plate) ofthe mother liquor to ˜80 mL produced a second crop (0.81 g, 2.5%) of3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one (19); mp 81.5°-82.0° C.The total yield was (15.47 g, 48.3%).

A 70-mL, five-necked, jacketed flask was equipped with a magneticstirrer, a heating mantle, a standard condenser, a lower take-offcondenser with a N₂ inlet, a thermometer, and two glass stoppers. Afterthe addition of the ketone (19, 2.0 g, 6.24 mmol), KOH pellets (85%,4.94 g, 56.1 mmol) and hydrazine (95%, 2.11 g, 32.1 mmol) in triethyleneglycol (40 mL) were added. The apparatus was flushed with N₂, and themixture was heated at 140°-150° C. for 4 h using boiling o-xylene (bp144° C.) in the jacket. Cooling the solution to RT was followed by theaddition of chilled water (80 mL). Combined extracts (ether, 3×75 mL) ofthe suspension were washed with saturated NaCl (75 mL), dried (Na₂ SO₄,overnight), filtered, and concentrated to a yellow oil (1.83 g, 95.7%)which displayed no carbonyl stretch in the IR spectrum. This oil, thatis amine (37), was used without further purification.

A 100-mL, three-necked, round-bottomed flask was equipped with amagnetic stirrer, a condenser with a N₂ inlet, a 50-mL addition funnel,and a glass stopper. To a solution of NaIO₄ (2.49 g, 11.62 mmol) in H₂ O(22.4 mL) was added RuO₂ ×H₂ O (0.1 g) which produced a dark greensolution. After the apparatus was flushed with N₂, a solution of theamine (37, 0.89 g, 2.9 mmol) in CCl₄ (16 mL) was added in one portion toproduce a black mixture. The mixture was stirred at RT for 72 h and thenthe organic layer was separated. Further extraction of the aqueous phasewas effected with CCl₄ (20 mL) followed by HCCl₃ (3×20 mL). Combinedextracts were treated with isopropyl alcohol (3 mL) to destroy excessoxidant and were then filtered through a celite pad. After washing theextracts with 5% sodium thiosulfate (50 mL), the extracts were dried(Na.sub. 2 SO₄, overnight), filtered, and concentrated to a yellow oil.Elution of the oil on neutral alumina (84 g, 2.4 cm×19 cm) using firstether (50 mL) and then ethyl acetate (150 mL) as eluants gave a solidmaterial (R_(f) =0.60, ethyl acetate). This material was recrystallizedby dissolving in ether (6 mL) and then refrigerating at -10° C. for 2 h;this solution was placed in a diffusion chamber of pentane for 1 h.Filtration afforded (0.27 g, 28.9%) of the lactam (17); mp 96.0°-96.5°C. IR (KBr) cm⁻¹ 3070, 3050, 3020 (Ar C--H), 2945, 2920, 2855, 2785,2760 (C--H), 1645 (C═O), 1600 (C═C) 740, 710 (C--H out of plane, mono);¹ H NMR (DCCl₃) δ1.69 [d, 1H, H(9), J=12.7 Hz], 1.88 [d, 1H, H(9 ),J=12.7 Hz], 2.05-2.09 [m, 2H, ring proton and H(1)], 2.24 (dd, 1H, ringproton, J=10.74 Hz, J'=2.66 [m, 2H, ring proton and H(5)], 3.08 [d, 1H,ring proton, J=11.8 Hz], 3.25-3.36 [m, 3H, ring proton and H(11)], 3.59[d, 1H, H(11), J=13.2 Hz], 4.24 [d, 1H, H(10), J=14.8 Hz], 5.06 [d, 1H,H(10), J=14.7 Hz], 7.08-7.38 (m, 10H, Ar--H); ¹³ C NMR (DCCl₃) ppm 27.94[C(9)], 28.07 [C(5)], 39.07 [C(1)], 49.84 [C(10)], 51.60 [C(4)], 57.07[C(8)], 59.03 [C(6)], 62.70 [C(11)], 126.88, 127.14, 128.17, 128.40,128.49, 128.72, 137.39, 138.13 (Ar--C), 172.77 (C═O). Anal. Calcd. forC₂₁ H₂₄ N₂ O; C, 78.72; H, 7.55. Found: C, 78.39; H, 7.78.

EXAMPLE XXXII 7-Benzyl-9,9-dimethoxy-3-thia-7-azabicyclo[3.3.1]-nonaneHydroperchlorate (11)

Caution: The use of shields, protective goggles and gloves is verystrongly recommended when performing this experiment. The formation ofexplosive methyl perchlorate is a likely side reaction in thisexperiment. No difficulty was noted when the reaction was performed asdescribed, but this may have been fortuitous. A one-necked, 100-mL,round-bottomed flask was fitted with a Soxhlet containing 3A molecularsieves (30 g), a condenser, a heating mantle, a magnetic stirrer, and aheating mantle. The effective cycling volume of the Soxhlet wasapproximately 15 mL. The flask was charged with a solution of the ketone(18, 1.0 g, 4 mmol) in methanol (20 mL) and benzene (20 mL). To thissolution was added HClO₄ (60%, 2.0 g, 12 mmol) in one portion. Theapparatus was flushed with N₂ and the pale yellow solution was heated atreflux with stirring and cycling through the Soxhlet for 24 h. Thesolution was cooled to RT and concentrated to about 5 mL. Ethyl ether(20 mL) was added, thus precipitating the salt as a powder. This wasfiltered, washed with ether (5 mL), and dissolved in hot methanol (20mL, decolorizing carbon). Trituration with ether (25 mL), followed bystanding for 24 h, afforded the salt (11) (0.74 g, 46.2%) as small whitecrystals; mp 193°-194° C. (dec); IR (KBr) cm⁻¹ 2800-2600 (N--H), 1090(Cl--O); ¹ H NMR (DMSO-d₆) δ2.58 [bs, 2H, H(1,5)], 2.75 [d, 2H,H(2,4)_(ax), J=14 Hz], 3.15-3.18 [m, 8H, H(2,4)_(eq) and OCH₃ ], 3.38[dd, or bt, 2H, H(6,8)_(ax), J=12 Hz], 3.60 [d, 2H, H(6,8)_(eq), J=12Hz], 4.33 (d, 2H, CH₂ Ph, J=5 Hz), 7.49-7.62 (m, 5H, Ar--H); ¹³ C NMR(DMOS-d₆) ppm 28.8 [t, C(2,4)], 32.2 [d, C(1,5)], 46.6 (q, OCH₃), 47.0(q, OCH₃), 54.5 [t, C(6,8)], 60.2 (t, CH₂ Ph), 95.1 [s, C(9)], 129.0,129.5, 130.1, 130.2 (d, Ar--C); ¹⁵ N NMR (DMSO-d₆) ppm 53.5 [N(7)].Anal. Calcd. for C₂₆ H₂₄ ClNO₆ S: C, 48.79; H, 6.14; Cl, 9.00; N, 3.56;S, 8.14. Found: C, 48.73; H, 6.09; Cl, 9.39; N, 3.54; S, 8.40.

EXAMPLE XXXIII 3,7-Dibenzyl-9,9-dimethoxy-3,7-diazabicyclo[3.3.1]nonaneHydroperchlorate (12)

Caution: The use of shields, protective goggles and gloves is verystrongly recommended when performing this reaction. The formation ofexplosive methyl perchlorate is a likely side reaction in thisexperiment. No difficulty was noted when the experiment was performed asdescribed, but this may have been fortuitous. A one-necked, 100-mL,round-bottomed flask was equipped with a Soxhlet containing 3A molecularsieve (30 g), a condenser with a N₂ inlet, a magnetic stirrer, and aheating mantle. The effective cycling volume of the Soxhlet wasapproximately 20 mL. The flask was charged with a solution of the ketone(19, 1.0 g, 3.12 mmol) in CH₃ OH (25 mL) and benzene (25 mL) to whichwas added HClO₄ (60%, 1.5 g, 8.96 mmol) in one portion. The apparatuswas flushed with N₂ and the colorless solution was heated to reflux withcycling through the Soxhlet. After 24 h, the now pale yellow solutionwas cooled to RT and concentrated to a white solid which was filtered,washed with C.sub. 6 H₆ (10 mL), and recrystallized (CH₃ OH, 80 mL) toafford the monoperchlorate (0.91 g) as small white crystals, mp223.6°-224.0° C. (dec). The mother liquor was concentrated toapproximately 10 mL. Upon cooling to a -10° C. overnight, a second cropof salt (12) was obtained (89.4 mg, 68.6% total), mp 219°-220° C. (dec).The spectral data were as follows: IR (KBr) cm⁻¹ 2800-2600 (N-H), 1100(Cl--O); ¹ H NMR (DMSO-d₆) δ2.35 [bs, 2H, H(1,5)], 2.90 [d, 4H,H(2,4,6,8)_(ax), J=13 Hz], 3.08 [d, 4H, H(2,4,6,8)_(eq), J=13 Hz], 3.14(s, 6H, OCH₃), 3.88 (s, 4H, CH₂ Ph), 7.38-7.54 (m, 10H, Ar--H), 9.84(bs, 1H, N-H); ¹³ C NMR (DMSO-d₆) ppm 33.0 [d, C(1,5)], 47.0 (q, OCH₃),53.8 [t, C(2,4,6,8)], 59.6 (t, CH₂ Ph), 95.4 [C(9)], 128.2, 128.4,129.6, 133.5 (Ar--C); ¹⁵ N NMR (DMSO-d₆) ppm 52.9 [N(3,7)]. Anal. Calcd.for C₂₃ H₃₁ ClN₂ O₆ : C, 59.16; H, 6.69; Cl, 7.59; N, 6.00. Found: C,58.98; H, 6.81; Cl, 7.86; N, 6.28.

EXAMPLE XXXIV 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane 3-Oxide (49)

A 200-mL flask was equipped with a magnetic stirrer, an ice bath, and acondenser with nitrogen inlet. To a stirred, chilled (5° C.) solution ofthe amine (27, 1.4 g, 6 mmol) in methanol (60 mL) was added dropwise asolution of NaIO₄ (1.35 g, 6.3 mmol) in water (15 mL) over 30 min. Afterstirring for one hour, the suspension was filtered and washed withmethanol (50 mL); the washings and filtrate were combined andconcentrated to a residue which was partitioned between H₂ CCl₂ andwater (40 mL each). Additional extracts (HCCl₃, 3×40 mL) of the aqueouslayer were combined with the initial extract, and the solution was dried(Na₂ SO₄) and concentrated to afford an oil which solidified uponstanding. Recrystallization (HCCl₃ /pentane) of the solid gave 1.15 g(76.9%) of crystalline (49); mp 140°-141° C. IR (KBr) cm⁻¹ 3085, 3065,3030, 2955, 2920, 2895, 2815, 1495, 1020, 740, 705; ¹ H NMR (DCCl₃)δ1.59 [bd, 1H, H(9), J=13.3 Hz], 1.86 [bd, 1H, H(9), J=13.2 Hz], 2.20[d, 2H, H(2,4)_(ax), J=11.7 Hz], 2.37 bs, 2H, H(1,5)], 2.62 [d, 2H,H(6,8)_(ax), J=12.0 Hz], 2.78 [d, 2H, H(2,4)_(eq), J=11.8 Hz], 3.51 [d,2H, H(6,8)_(eq), J=11.7 Hz], 3.55 [s, 2H, ArCH₂ ], 7.26-7.39 (m, 5H,Ar--H); ¹³ C NMR (DCCl₃) ppm 31.86 [t, C(9)], 32.59 [d, C(1,5)], 57.42[t, C(2,4)], 58.59 [C(6,8)], 62.88 (ArCH₂), 127.20, 128.39, 129.12,137.67; ¹⁵ N NMR (DCCl₃) ppm 49.37 [N(7)]. Anal. Calcd. for C₁₄ H₁₉ NOS:C, 67.43; H, 7.68. Found: C, 67.61; H, 7.73.

EXAMPLE XXXV 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonane 3-OxideHydroperchlorate (10)

A 50-mL Erlenmeyer flask was equipped with a magnetic stirrer and an icebath. To a stirred, chilled (5° C.) solution of the sulfoxide (49, 0.47g, 1.88 mmol) in ether (20 mL) and isopropyl alcohol (3 mL) was addeddropwise a solution of HClO₄ (60%, 0.63 g, 3.75 mmol) in isopropylalcohol (3 mL) over 30 min. Filtering of the precipitate followed, andlatter was washed with ether (50 mL) and then recrystallized (95%ethanol) to give a crystalline salt (10) (0.51 g, 78.1%); mp 137°-138°C. IR (KBr) cm⁻¹ 3090, 2970, 2950, 1465, 1095, 745, 705; ¹ H NMR (D₃COD) δ1.70 [bd, 1H, H(9), J=14.0 Hz], 2.01 [bd, 1H, H(9), J=13.9 Hz[,2.61 [bd, 2H, H(2,4)_(ax), J=11.8 Hz], 2.69 [bs, 2H, H(1,5)], 3.06 [bd,2H, H(2,4)_(eq), J=11.8 Hz], 3.36 [bd, 2H, H(6,8)_(ax), J=13.1 Hz], 3.94(s, 2H, ArCH₂), 4.19 [bd, 2H, H(6,8)_(eq), J=12.9 Hz], 7.35-7.42 (m, 5H,Ar--H); ¹³ C NMR (D₃ COD) ppm 30.80 [C(9)], 36.27 [C(1,5)], 53.94[C(2,4)], 58.56 [C(6,8)], 61.07 [ArCH₂ ], 129.43 129.78, 131.49, 135.29;¹⁵ N NMR (DMSO-d₆) ppm 56.45 [N(7)]. Anal. Calcd. for C₁₄ H₂₀ ClNSO₅ :C, 48.06; H, 5.76. Found: C, 47.84; H, 5.74.

EXAMPLE XXXVI 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one 6,8,10-¹⁴C₃ (18)*

Caution: Special precautions should be taken when handling radioactivechemicals. All reactions should be carried out in a well ventilated hoodwith protective shields to prevent possible contamination of the labarea. Protective safety goggles as well as quality rubber gloves shouldalso be worn at all times since exposure to the ¹⁴ C materials could bedangerous. A 50-mL, three-necked, round-bottomed flask was equipped witha magnetic stirrer, a heating mantle, a condenser with a N₂ inlet, andtwo glass stoppers. To a mixture containing benzylamine (0.43 g, 4mmol), [¹⁴ C] benzylamine HCl [1 mg, 7×10⁻³ mmol, 0.5 mCi (minimumactivity, ICN)] in H₂ O (2.5 mL), and deoxygenated methanol (15 mL) wasadded HCl (37%, 0.1 g, 1 mmol) followed by glacial acetic acid (0.36 g,6 mmol). Addition in one portion of paraformaldehyde (0.96 g, 32 mmol)and [¹⁴ C] paraformaldehyde [1 mg, 3.3×10⁻ 2 mmol, 0.5 mCi (minimumactivity, ICN)] was followed by subsequent addition of 4-thianone (43,0.47 g, 4 mmol) all at once with stirring. After the mixture was heatedat reflux under N₂ for 6 h, the solution was concentrated to 2-3 mL andthen diluted with H₂ O (30 mL). The aqueous solution was extracted withether (2×30 mL), and the latter was discarded. Chilling (via ice waterbath) of the aqueous layer to below 5° C. was followed by basification(pH˜12) with NaOH pellets (97%, 0.29 g, 7 mmol) which resulted in theformation of a cloudy suspension. Combined extracts (ether, 4×30 mL)were dried (Na₂ SO₄, overnight), filtered, and concentrated (rotaryevaporator) to give a viscous oil, which was then digested in 200 mL ofSkelly B (bp 60°-68° C.) for 0.5 h. Concentration of the supernatantafforded a yellow oil which was subjected to heating at high vacuum(110° C./0.1 mm Hg) in a sublimation apparatus to give 0.13 g of ketone(18)*; mp 91°-93° C. The residue which remained was again dissolved inether (˜50 mL), and the latter solution was dried (Na₂ SO₄, overnight),filtered, and concentrated to an oil. Digestion of the oil was effectedin 50 mL of Skelly B for 0.5 h, and the supernatant was concentrated toa viscous oil. This material was heated under vacuum (110° C./0.1 mm Hg)in a sublimation apparatus and gave 0.05 g of slightly crude ketone(18)*; mp 78°-80° C. A mixture melting point determination with thefirst crop was 86°-88° C. without significant depression. This gave atotal yield of 0.18 g (17.7%) of ketone (18)* which was used withoutfurther purification in the next step.

EXAMPLE XXXVII 7-Benzyl-3-thia-7-azabicyclo[3.3.1]nonaneHydroperchlorate 6,8,10-¹⁴ C₃ (48)*

Caution: Special precautions should be taken when handling radioactivechemicals. All reactions should be carried out in a well ventilated hoodwith protective shields to prevent possible contamination of the labarea. Protective safety goggles as well as quality rubber gloves shouldalso be worn at all times since exposure to the ¹⁴ C materials could bedangerous. To a mixture of KOH pellets (85%, 0.48 g, 8.5 mmol) and theketone (18)* (0.18 g, 0.71 mmol) in triethylene glycol (5 mL) was addedhydrazine (95%, 0.23 g, 7.1 mmol) in one portion in a 50-mL, jacketedflask equipped with a magnetic stirrer, a condenser, a lower take-offcondenser and two glass stoppers. A heating temperature of 140°-150° C.for 4 h was produced by boiling o-xylene (bp 144° C.) in the jacket.After cooling to RT, the solution was diluted with chilled H₂ O (30 mL)and extracted with ether (4×20 mL). Combined extracts were dried (Na₂SO.sub. 4, overnight) and filtered. Cooling of the ethereal solution tobelow 5° C. was followed by the dropwise addition of HClO₄ (60%, 1 mL)over 10 min with stirring, which resulted in the formation of a whiteprecipitate. Crude salt (48)* was filtered, recrystallized (95% EtOH),and dried over P₂ O₅ (78° C./0.1 mm Hg) to give 0.14 g (58.6%) of whitecrystals of salt (48)*; mp 154.5°-155.0° C.; (lit 155°-156° C.). A stocksolution (3.49 mg/mL) of salt (48)* was prepared using DMSO, H₂ O, and0.1N HCl (40:53.5:6.5 by volume). Samples were made by diluting 4 μL ofthe stock solution with 10 mL of Aquasol 2 scintillation cocktail (NewEngland Nuclear Research Products). Measurements of activity wereobtained at room temperature using a TRI-CARB liquid scintillationanalyzer, model 1900 CA (Packard Instrument Company). An average countof 19,800 DPM was observed for each sample and the specific activity wasdetermined to be 0.64 μCi/mg. In similar fashion, samples were preparedfrom stock solution of the salt (48)* in methanol and the specificactivity was determined to be 0.63 μCi/mg.

To illustrate the useful biological properties of the compoundsdescribed in this invention, selected derivatives were screened forantiarrhythmic activity using dog models. The clinically used agentlidocaine and 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate(48) [U.S. Pat. No. 4,581,361] were employed as standards as basis forcomparison. A small infarction was created in an area of the dog heartand thereafter electrical pacing was initiated to generate a sustainedventricular tachycardia (VT). This irregular beating pattern of theheart results in a reduction of the pumping capability of the heart in amanner now accepted as resembling symptoms observed in humans during aheart attack (see: Scherlag, B. J. et. al., Am. J. Cardiol. 1983, 51,207; Bailey, B. R. et. al., J. Med. Chem. 1984, 27, 759; Thompson, M. D.et. al., J. Med. Chem. 1987, 30, 780; U.S. Pat. No. 4,581,361; and U.S.Pat. No. 4,778,892 for further details, said references incorporatedherein for such purposes). The effects of the selected compounds interms of ability to reduce the rate of the induced VT or to eliminatethe same (abolish the VT completely or at least not allow it to besustained) is then evaluated and compared to lidocaine or to7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate (48). Sincethe latter hydroperchlorate proved superior to lidocaine in most of thestudies, data in Table A are compared to that obtained for the salt (48)cited herein. In Table A, it is clear that salts (1), (3), (5), (11),(13), and (14) are extremely effective in eliminating the induced VT aswas the standard 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonanehydroperchlorate (48) at 3 mg/kg as well as at 6 mg/kg. Salts (10),(12), (15), and (17) reduced the rates of the induced VT but did notabolish them. In contrast, salt (8) exhibited little effect on the dogmodel which suggests there exists a high degree of specificity of actionof these molecules in terms of antiarrhythmic activity. Thus, theseheterocyclic molecules claimed in this application haveelectrocardiology properties equal or superior to those of the standard7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate (48) which isknown to have such superior properties to those of lidocaine (see: U.S.Pat. Nos. 4,581,361 and 4,778,891) which is a clinically used agent forthe treatment of victims of heart attacks.

In principle, it is felt that the compositions of the present inventioncan be employed separately or incombination with each other or incombination with other drugs to achieve either individually or incombination the desired antiarrhythmic properties. It is expected thatthe composition can be utilized and administered via a variety ofmethods including by way of an example, but not limited thereto,intravenously, orally, by suppository, by inhalation, and the like.Furthermore, it is generally felt that the compositions as claimedeither specifically possess antiarrhythmic activity or generally arebroad biologically active or the respective compositions areintermediates to antiarrhythmic and biologically active species that arereleased or created in situ as the result of administration of the drug.

                                      TABLE A                                     __________________________________________________________________________    ANTIARRHYTHMIC PROPERTIES                                                     OF REPRESENTATIVE 3-AZABICYCLO[3.3.1]NONANE SALTS                              ##STR12##                                                                                                  (Effect on SVT.sup.b)                           Comp.sup.a                                                                          R     Y           Z     3mg/kg                                                                              6mg/kg                                    __________________________________________________________________________    (1)   CH(CH.sub.3).sub.2                                                                  NC(O)Ph     CH.sub.2                                                                            NSVT  NSVT                                      (3)   CH(CH.sub.3).sub.2                                                                  NCH.sub.2 C.sub.6 H.sub.4 -3,4(OCH.sub.3).sub.2                                           CH.sub.2                                                                            NSVT  NSVT                                      (5)   CH(CH.sub.3).sub.2                                                                  NCH.sub.2 Ph                                                                              CH.sub.2                                                                            NSVT  NSVT                                      (8)   CH(CH.sub.3).sub.2                                                                  S           CH.sub.2                                                                            No action                                                                           No action                                 (Stand.-48)                                                                         CH.sub.2 Ph                                                                         S           CH.sub.2                                                                            NSVT.sup.c                                                                          NSVT                                      (10)  CH.sub.2 Ph                                                                          ##STR13##  CH.sub.2                                                                            Reduced rate of VT                                                                  Reduced rate of VT                        (11)  CH.sub. 2 Ph                                                                        S           C(OCH.sub.3).sub.2                                                                  NSVT  NSVT                                      (12)  CH.sub.2 Ph                                                                         NCH.sub.2 Ph                                                                              C(OCH.sub.3).sub.2                                                                  Reduced                                                                             Reduced                                                                 rate of VT                                                                          rate of VT                                (13)  CH.sub.2 PH                                                                         CHCO.sub.2 Et                                                                             CH.sub.2                                                                            NSVT  NSVT                                      (14)  CH.sub.2 Ph                                                                         CHCO.sub.2 Et                                                                             C(SCH.sub.2).sub.2                                                                  NSVT  NSVT                                      (15)  NC(O)Ph                                                                             S           CH.sub.2                                                                            Reduced                                                                             Reduced                                                                 rate of VT                                                                          rate of VT                                (17).sup.d                                                                          CH.sub.2 Ph                                                                         NCH.sub.2 Ph                                                                              CH.sub.2                                                                            Reduced                                                                             Reduced                                                                 rate of VT                                                                          rate of VT                                __________________________________________________________________________     .sup.a X = ClO.sub.4, Cl, Br, citrate, fumarate, HSO.sub.4                    .sup.b SVT = Sustained ventricular tachycardia induced by electrical          pacing of infarcted dog heart                                                 .sup.c NSVT = Nonsustained ventricular tachycardia (or abolished              ventricular tachycardia)                                                      .sup.d All compounds have Q is CH.sub.2 except (17) where Q is CO        

In order to determine the potential viability of members of the abovefamily to act as useful antiarrhythmic agents in vivo, a pharmacokineticand metabolism study was undertaken using a representative example fromthe above compounds. The techniques employed in these preliminarystudies are well documented, but a summary of pharmacokinetic procedurescan be found in: J. D. Baggot, "Principals of Drug Disposition inDomestic Animals: The Basis of Veterinary Clinical Pharmacology", W. B.Saunders Company, Philadelphia, 1977. These studies were conducted using¹⁴ C-labelled (48)* [Prepared by the method of Zisman, Berlin, et al. J.Labelled Compounds and Radiopharmaceuticals, In Press (1989)] inSprague-Dawley rats.

Radioactivity-time data obtained by analysis of blood samples collectedafter intracardiac or oral administration are recorded in Tables B and Cso designated. Coefficients and exponents of the disposition curveswhich best described changes in blood radioactivity with time afteradministration were obtained using a microcomputer program [R. D. Brownet al. J. Pharmaceutical Sciences, 67, 1687 (1978)]. The disposition of(48)* after intracardiac administration was well described by atwo-compartment open model and the pharmacokinetic parameters derivedfrom the analysis of individual blood radioactivity data are presentedin Table D so designated. The median half-life of elimination(T_(1/2)(β)) of radioactivity was 5.7 hours, which suggested that amoderate to reasonably long dosage interval might be appropriate fortherapeutic use. The median apparent volume of distribution, based ontotal area under the disposition curve (V_(d)(area)), was high (4070ml/kg) indicating extensive distribution into body tissues. The hightotal body clearance value (Cl_(B) =470) confirms the presence ofefficient drug elmination pathways.

Pharmacokinetic terms describing changes in blood radioactivity afteroral administration are presented in Table D so designated.Compartmental analysis showed that the data fitted a one-compartmentpharmacokinetic model. Oral dosing resulted in rapid and extensiveabsorption and peak concentrations within 30 minutes afteradministration. The ratio of the areas under the radioactivity-timecurves obtained after oral and intracardiac administration (AUC_(po)/AUC_(ic)) indicates a high bioavailability (±81%). Thus, the oral routeof administration may be suitable for therapeutic management of patientssuffering from cardiac arrhythmias.

                                      TABLE B                                     __________________________________________________________________________    Kinetics of appearance of radioactivity [dpm/ml] in blood                     after intracardiac administration of a bolus dosage                           (10 mg/kg) of (48)*(1332000dpm/mg).                                           Time after                                                                    administration                                                                       Individual rats                                                        (hours)                                                                              #2 #3 #8 #9 #10                                                                              #15                                                                              #16                                                                              Mean                                                                              SD                                            __________________________________________________________________________     0.0333                                                                              -- 6802                                                                             6732                                                                             6419                                                                             6173                                                                             6595                                                                             7140                                                                             6644                                                                              333                                            0.0833                                                                              5482                                                                             5424                                                                             -- 5496                                                                             5661                                                                             6106                                                                             7262                                                                             5905                                                                              710                                            0.1667                                                                              4741                                                                             5520                                                                             6087                                                                             4903                                                                             4780                                                                             5752                                                                             6435                                                                             5460                                                                              674                                            0.3333                                                                              4807                                                                             4225                                                                             -- 4261                                                                             4768                                                                             5219                                                                             6197                                                                             4913                                                                              731                                            0.5   -- 5294                                                                             3233                                                                             4210                                                                             4228                                                                             5152                                                                             3938                                                                             4343                                                                              773                                            1     2911                                                                             3619                                                                             4182                                                                             4343                                                                             3002                                                                             3433                                                                             3873                                                                             3623                                                                              551                                            2     1862                                                                             2004                                                                             2495                                                                             2451                                                                             2721                                                                             2463                                                                             1907                                                                             2272                                                                              340                                            3     -- 1307                                                                             2357                                                                             2369                                                                             2314                                                                             -- -- 2087                                                                              520                                            4     1374                                                                             1382                                                                             2316                                                                             2429                                                                             2379                                                                             1578                                                                             1438                                                                             1842                                                                              504                                            6     -- 1719                                                                             2089                                                                             1905                                                                             2186                                                                             1690                                                                             1377                                                                             1828                                                                              295                                           10     1005                                                                             1113                                                                             1123                                                                             1191                                                                               903                                                                            1040                                                                              900                                                                             1039                                                                              112                                           16     --  534                                                                              332                                                                              515                                                                              353                                                                              395                                                                              349                                                                              413                                                                               89                                           24      242                                                                              308                                                                              71                                                                               60                                                                               178                                                                              197                                                                              144                                                                              171                                                                               89                                           __________________________________________________________________________

                  TABLE C                                                         ______________________________________                                        Kinetics of appearance of radioactivity [dpm/ml] in blood                     after oral administration of a bolus dosage                                   (10 mg/kg) of (48)*(1332000dpm/mg).                                           Time                                                                          after                                                                         admin-                                                                        istra-                                                                        tion  Individual rats                                                         (hours)                                                                             #4     #6     #7   #11  #12   #13  Mean  SD                             ______________________________________                                         0.1667                                                                             1928    802   1026 1601 479    967 1134  534                             0.3333                                                                             2153   1723   2311 3265 754   1946 2025  818                             0.5  4281   2086   2659 4421 1025  2151 2771  1335                            1    3895   1911   2272 3154 958   2106 2383  1022                            2    2208   1545   1618 2896 991   2043 1884  654                             4    1786   2034   2114 2017 1767  1713 1905  169                             6    1601   1502   1224 1594 1714  1138 1462  230                            10     893    662    885 1118 1613   984 1026  324                            16     418    245    302  140 586    390  347  154                            24     300    89     79   66  197    75   134   95                            ______________________________________                                    

                                      TABLE D                                     __________________________________________________________________________    Pharmacokinetic values derived from each rat's (48)* blood disposition        curves.                                                                       __________________________________________________________________________    I. Intracardiac administration:                                                       Inidividual rats                                                      Determinant                                                                           2   3   8   9   10  15  16  Mean                                                                              SD                                    __________________________________________________________________________    A (dpm/ml)                                                                            3670                                                                              3924                                                                              2583                                                                              2532                                                                              2350                                                                              3852                                                                              5097                                                                              3330                                                                               966                                  B (dpm/ml)                                                                            2192                                                                              2152                                                                              4333                                                                              4647                                                                              3659                                                                               2972.                                                                            2652                                                                              1616                                                                              1808                                  α (hr.sup.-1)                                                                   1.36                                                                              0.86                                                                              1.93                                                                              11.49                                                                             2.18                                                                              1.48                                                                              1.62                                                                              1.55                                                                              2.96                                  β (hr.sup.-1)                                                                    0.090                                                                             0.080                                                                             0.163                                                                             0.164                                                                             0.131                                                                             0.115                                                                             0.121                                                                             0.124                                                                             0.035                                 K.sub.21 (hr.sup.-1)                                                                  0.568                                                                             0.359                                                                             1.276                                                                             7.499                                                                             1.380                                                                             0.710                                                                             0.636                                                                             1.775                                                                             2.551                                 K.sub.el (hr.sup.-1)                                                                  0.217                                                                             0.194                                                                             0.248                                                                             0.252                                                                             0.207                                                                             0.241                                                                             0.310                                                                             0.238                                                                             0.038                                 K.sub.12 (hr.sup.-1)                                                                  0.673                                                                             0.394                                                                             0.578                                                                             3.908                                                                             0.726                                                                             0.646                                                                             0.800                                                                             1.103                                                                             1.243                                 t.sub.1/2(β) (hr)                                                                7.67                                                                              8.60                                                                              4.23                                                                              4.20                                                                              5.28                                                                              5.99                                                                              5.70*                                         t.sub.1/2(α) (hr)                                                               0.50                                                                              0.79                                                                              0.35                                                                              0.06                                                                              0.31                                                                              0.46                                                                              0.42*                                         C.sub.o 5863m/ml)                                                                         6077                                                                              6917                                                                              7179                                                                              6010                                                                              6824                                                                              7750                                                                              6660                                                                               701                                  V.sub.c (ml/kg)                                                                       2271                                                                              2191                                                                              1925                                                                              1855                                                                              2216                                                                               1951*                                                                            1718                                          V.sub.d(area) (ml/kg)                                                                 5471                                                                              5291                                                                              2926                                                                              2843                                                                              3504                                                                               4070*                                                                            4390                                          V.sub.d(ss) (ml/kg)                                                                   4963                                                                              4596                                                                              2798                                                                              2822                                                                              3381                                                                               3725*                                                                            3879                                          Cl.sub.B (ml/hr · kg)                                                         494                                                                               426                                                                               478                                                                               468                                                                               459                                                                               470*                                                                              533                                          AUC.sub.ic                                                                            25282                                                                             27480                                                                             29169                                                                             30489                                                                             28444                                                                             27126                                                                             24104                                                                             27442                                                                             2205                                  __________________________________________________________________________    I. Oral administration:                                                               Individual rats                                                       Determinant                                                                           4   6   7    11  12   13  Mean SD                                     __________________________________________________________________________    β (hr.sup.-1)                                                                    0.107                                                                             0.138                                                                             0.143                                                                              0.181                                                                             0.149                                                                              0.137                                                                             0.143                                                                              0.023                                  t.sub.1/2(β) (hr)                                                                6.42                                                                              5.00                                                                              4.81 3.80                                                                              4.63 5.04                                                                              4.90*                                       AUC.sub.po                                                                            25306                                                                             18755                                                                             20243                                                                              24510                                                                             24383                                                                              20555                                                                             22292                                                                              2760                                   AUC.sub.po /AUC.sub.ic             0.81233                                    __________________________________________________________________________     *Values represent medians                                                

Tissue distribution of (48)* was studied by measuring the radioactivityin selected organs collected from rats sacrificed at several timeintervals after oral administration. Data obtained from these studies isreported in Table E so designated. High levels of radioactivity weremeasured in liver and kidney which is consistent with the extensivemetabolism and excretion of metabolites commonly encountered with highlylipid soluble xenobiotics [agent (48)* has both polar and nonpolarstructural features]. These observations correlate well with the highvolume of distribution calculated from pharmacokinetic data. Reasonablyhigh concentrations of radioactivity in the heart confirm that (48)*achieves good penetration into the target organ. Radioactivity in thebrain and perirenal fat were low in comparison with other tissues anddecreased steadily with time after administration. This suggests thatcentral neurotoxicity may not limit the therapeutic use of these agentsand that long-term accumulation in fat depots may not present atoxicological hazard.

Thin layer chromatographic analysis of urine samples collected afteroral administration of ¹⁴ C-labelled (48)* to rats indicated that mostof the dose was excreted in the form of metabolites. Using massspectrometry, the major metabolite was identified as ¹⁴ C-labelled(15)*, the structure of which was confirmed by comparison with anauthenticated sample of unlabelled (15). Consequently, amide (15) is anactive metabolite of (48) and is therefore a potentially viable agent inits own right.

                  TABLE E                                                         ______________________________________                                        Concentration of radioactivity in selected organs                             and tissues after oral administration of a bolus                              dosage (10 mg/kg) of (48)*(1332000dpm/mg).                                    Time after                                                                    adminis-                                                                              Experimental units                                                    tration (hr)                                                                          I        II       III    Mean   SD                                    ______________________________________                                        I. Blood concentrations (dpm/ml):                                                0.083                                                                              2330     1970     3975   2758   1069                                    0.25  5170     6755     4615   5513   1111                                    0.5   6020     6010     4935   5655    624                                    0.75  4370     3335     4245   3983    565                                    1.5   2840     2790     3300   2977    281                                  4       2060     2580     1800   2147    397                                  8        740      650      740    710    52                                   16       276      219      295    263    40                                   ______________________________________                                        I. Kidney concentrations (dpm/g):                                                0.083                                                                              11320    5425     21341  12695  8047                                    0.25  27222    34142    20528  27297  6807                                    0.5   31622    39516    28700  33279  5595                                    0.75  26793    19249    24987  23676  3939                                    1.5   18881    16254    21566  18900  2656                                  4       15219    17715    12217  15050  2753                                  8       4963     4835     5296   5031    238                                  16      2591     1761     2285   2212    420                                  24      1250     2489     1004   1581    796                                  ______________________________________                                        I. Liver concentrations (dpm/g):                                                 0.083                                                                              49025    37302    33768  40032  7986                                    0.25  77479    86705    53662  72615  17050                                   0.5   82327    81324    68846  77499  7510                                    0.75  40648    16117    46449  34405  16101                                   1.5   14156    18970    21791  18306  3861                                  4       14430    17811    15814  16018  1700                                  8       10272    9195     9855   9774    543                                  16      6886     4065     4948   5300   1443                                  24      3427     4709     2563   3566   1080                                  ______________________________________                                        I. Heart concentrations (dpm/g):                                                 0.083                                                                              4813     1236     4292   3447   1932                                    0.25  5402     5647     3890   4980    952                                    0.5   5071     4903     4107   4694    515                                    0.75  3442     2785     3608   3278    435                                     1.5  2415     2511     2736   2554    165                                  4       1820     2114     1676   1870    223                                  8        826      668      790    761    83                                   16       336      273      412    340    70                                   24       221      320      184    242    70                                   ______________________________________                                        Perirenal fat concentrations (dpm/g):                                            0.083                                                                              2583      647     4670   2633   2012                                    0.25  16771    1925      926   6541   8874                                    0.5   1606     2068     2145   1940    292                                    0.75  1070     1866     2599   1845    765                                    1.5    718      933      745    799    117                                  4        610      508      562    560    51                                   8        577      172      558    436    229                                  16       216      138      271    208    67                                   24       77       119      97     98     21                                   ______________________________________                                        I. Brain concentrations (dpm/g):                                                 0.083                                                                              1280      296     1496   1024    640                                    0.25  1562     1980     1028   1523    477                                    0.5    824      971       643   813    164                                    0.75   711     1051      551    771    255                                    1.5    477      506      626    536    79                                   4        399      343      399    380    32                                   8        248      232      274    251    21                                   16       108      106      92     102     9                                   24       70       96       79     82     13                                   ______________________________________                                    

The 3-azabicyclo[3.3.1]nonane compounds described herein may begenerally characterized by the formula: ##STR14## wherein H-X representsa pharmacologically acceptable acid,

Q represents CH₂, or CO,

Z represents CH₂, CO, C(OCH₃)₂, or ##STR15## R represents hydrogen,lower alkyl, or a benzyl- or benzoyl group wherein the phenyl ring isunsubstituted or is substituted by halogen or by 1 to 3 methoxy groups,a benzene sulfonyl group, or ##STR16## and Y represents S, S→O, CH--CO₂C₂ H₅, or a group N--R' wherein R' is lower alkyl or a benzyl- orbenzoyl group, in which group the phenyl ring is unsubstituted or issubstituted by halogen or by 1 to 3 methoxy groups.

The claims and the specification describe the invention presented andthe terms that are employed in the claims draw their meaning from theuse of such terms in the specification. The same terms employed in theprior art may be broader in meaning than specifically employed herein.Whenever there is a question between the broader definition of suchterms used in the prior art and the more specific use of the termsherein, the more specific meaning is meant.

While the invention has been described with a certain degree ofparticularity it is manifest that many changes may be made in thedetails of construction and the arrangement of components withoutdeparting from the spirit and scope of this disclosure. It is understoodthat the invention is not limited to the embodiments set forth hereinfor purposes of exemplification, but is to be limited only by the scopeof the attached claim or claims, including the full range of equivalencyto which each element thereof is entitled.

What is claimed is:
 1. A 3-azabicyclo [3.3.1]nonane compound having thefollowing formula: ##STR17## wherein H-X represents a pharmacologicallyacceptable acid,Q represents CH₂, or CO, Z represents CH₂, CO, C(OCH₃)₂,or ##STR18## R represents hydrogen, lower alkyl, or a benzyl- or benzoylgroup wherein the phenyl ring is unsubstituted or is substituted byhalogen or by 1 to 3 methoxy groups, a benzene sulfonyl group, or##STR19## and Y represents S→O.
 2. A compound according to claim 1wherein Q represents CH₂.
 3. A compound according to claim 1 wherein Zrepresents CH₂.
 4. A compound according to claim 1 wherein R representsC₁ -C₄ -alkyl or an optionally substituted benzyl- or benzoyl group.